Compounds and methods for kinase modulation, and indications therefor

ABSTRACT

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

RELATED PATENT APPLICATIONS

This application is a U.S. Divisional Application of U.S. applicationSer. No. 11/473,347 filed Jun. 21, 2006, which claims the benefit ofU.S. Prov. App. No. 60/692,960, filed Jun. 22, 2005, and U.S. Prov. App.No. 60/731,528, filed Oct. 28, 2005, which are incorporated herein byreference in their entireties and for all purposes.

FIELD OF THE INVENTION

The present invention relates to kinases and compounds which modulatekinases, and uses therefor. Particular embodiments contemplate diseaseindications which are amenable to treatment by modulation of kinaseactivity by the compounds of the present invention.

BACKGROUND OF THE INVENTION

The information provided herein is intended solely to assist theunderstanding of the reader. None of the information provided norreferences cited is admitted to be prior art to the present invention.Each of the references cited herein is incorporated in its entirety.

Receptor protein kinases regulate key signal transduction cascades thatcontrol or are involved in the control of a plethora of physiologicalfunctions including cellular growth and proliferation, celldifferentiation, cellular development, cell division, cell adhesion,stress response, short-range contact-mediated axonal guidance,transcription regulation, aberrant mitogenesis, angiogenesis, abnormalendothelial cell-cell or cell-matrix interactions during vasculardevelopment, inflammation, lymphohematopoietic stem cell activity,protective immunity against specific bacteria, allergic asthma, aberranttissue-specific responses to the activation of the JNK signaltransduction pathway, cell transformation, memory, apoptosis,competitive activity-dependent synapse modification at the neuromuscularsynapse, immunological mediation of disease, and calcium regulation.

Specific disease states associated with aberrant regulation of proteinkinases include, for example without limitation, acrocephalo-syndactyltype I, acute myeloid leukemia, AIDS-induced non-Hodgkin's lymphoma,Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma,atherosclerosis, atopic dermatitis, autoimmune diseases, bacterialinfection, bladder cancer, cancer of the breast, cancer of the centralnervous system, cancer of the colon, cancer of the endometrium, cancerof the fallopian tube, cancer of the gastrointestinal tract, cancer ofthe ovary, heart failure, chronic myeloid leukemia, colon carcinoma,colorectal cancer, chronic obstructive pulmonary disease (COPD), CrouzonSyndrome, diabetes, diabetic nephropathy, emphysema, endometriosis,epidermoid cancer, fibrotic disorders, gastrointestinal stromal tumor(GIST), glomerulonephritis, Graves' disease, head injury, hepatocellularcarcinoma, Hirschsprung's disease, human gliomas, immunodeficiencydiseases, inflammatory disorders, ischemic stroke, Jackson-Weisssyndrome, leiomyosarcoma, leukemias, lupus nephritis, malignantmelanoma, malignant nephrosclerosis, mastocytosis, mast cell tumors,melanoma of the colon, MEN2 syndromes, metabolic disorders, migraine,multiple sclerosis, myeloproliferative disorders, nephritis,neurodegenerative diseases, neurotraumatic diseases, non small cell lungcancer, organ transplant rejection, osteoporosis, pain, Parkinson'sdisease, Pfeiffer Syndrome, polycystic kidney disease, primarylymphoedema, prostate cancer, psoriasis, vascular restenosis, rheumatoidarthritis, dermal and tissue scarring, selective T-cell defect (STD),severe combined immunodeficiency (SCID), small cell lung cancer, spinalcord injury, squamous cell carcinoma, systemic lupus erythematosis,testicular cancer, thrombotic microangiopathy syndromes, Wegener'sgranulomatosis, X-linked agammaglobulinemia, viral infection, diabeticretinopathy, alopecia, erectile dysfunction, macular degeneration,chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS),neurofibromatosis, and tuberous sclerosis. Accordingly, there is a needin the art for additional compounds and methods of use thereof for themodulation of receptor protein kinases.

This application is related to the following published patentapplications: WO 2004024895, US 20040142864, WO 2004078923, US20050170431, WO 2005028624, US 20050164300, and WO 2005062795, each ofwhich are hereby incorporated by reference herein in their entiretiesincluding all specifications, figures, and tables, and for all purposes.

SUMMARY OF THE INVENTION

The present invention concerns compounds active on protein kinases ingeneral, including, but not limited to, Abl, Akt1, Akt2, Akt3, ALK,Alk5, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,Flt3, Flt4, Fins, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4,IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr,Kit, LCK, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38,PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta,Plk1, Pyk2, Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA,Yes, and/or Zap70, including any mutations of these kinases, and the usethereof in treating disease and conditions associated with regulation ofthe activity of the kinase. In particular, the invention concernscompounds of Formula I as described below. Thus, the invention providesnovel use of compounds for therapeutic methods involving modulation ofprotein kinases, as well as novel compounds that can be used fortherapeutic methods involving modulation of protein kinases.

The compounds of Formula I have the following structure:

all salts, prodrugs, tautomers, and isomers thereof,

-   -   wherein:    -   R², R⁴, R⁵, and R⁶ are independently selected from the group        consisting of hydrogen, halogen, optionally substituted lower        alkyl, optionally substituted lower alkenyl, optionally        substituted lower alkynyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, —CN, —NO₂,        —CR^(a)R^(b)R²⁶, and -LR²⁶;    -   R³ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted lower        alkenyl, optionally substituted lower alkynyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —CN, —NO₂, —CR^(a)R^(b)R²⁶, -LR²⁶ and -A-Ar-L₁-R²⁴;    -   A is selected from the group consisting of —O—, —S—,        —CR^(a)R^(b)—, —NR¹—, —C(O)—, —C(S)—, —S(O)—, and —S(O)₂—;    -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)R⁷,        —C(S)R⁷, —S(O)₂R⁷, —C(O)NHR⁷, —C(S)NHR⁷, and —S(O)₂NHR⁷, wherein        lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, —OH,        —NH₂, lower alkoxy, lower alkylthio, mono-alkylamino,        di-alkylamino, and —NR⁸R⁹, wherein the alkyl chain(s) of lower        alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of        mono- or di-alkylamino is fluoro, further provided, however,        that when R¹ is lower alkyl, any substitution on the lower alkyl        carbon bound to the N of —NR¹— is fluoro, and wherein        cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally        substituted with one or more substituents selected from the        group consisting of halogen, —OH, —NH₂, lower alkyl, fluoro        substituted lower alkyl, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   R⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein        lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, —OH,        —NH₂, lower alkoxy, lower alklylthio, mono-alkylamino,        di-alkylamino, and —NR⁸R⁹, provided, however, that any        substitution of the alkyl carbon bound to the N of —C(O)NHR⁷,        —C(S)NHR⁷ or —S(O)₂NHR⁷ is fluoro, wherein the alkyl chain(s) of        lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino        are optionally substituted with one or more substituents        selected from the group consisting of fluoro, —OH, —NH₂, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of        mono- or di-alkylamino is fluoro, and wherein cycloalkyl,        heterocycloalkyl, aryl and heteroaryl are optionally substituted        with one or more substituents selected from the group consisting        of halogen, —OH, —NH₂, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino;    -   Ar is selected from the group consisting of optionally        substituted arylene and optionally substituted heteroarylene;    -   L at each occurrence is independently selected from the group        consisting of -(alk)_(a)-S-(alk)_(b)-, -(alk)_(a)-O-(alk)_(b)-,        -(alk)_(a)-NR²⁵-(alk)_(b)-, -(alk)_(a)-C(O)-(alk)_(b)-,        -(alk)_(a)-C(S)-(alk)_(b)-, -(alk)_(a)-S(O)-(alk)_(b)-,        -(alk)_(a)-S(O)₂-(alk)_(b)-, -(alk)_(a)-OC(O)-(alk)_(b)-,        -(alk)_(a)-C(O)O-(alk)_(b)-, -(alk)_(a)-OC(S)-(alk)_(b)-,        -(alk)_(a)-C(S)O-(alk)_(b)-, -(alk)_(a)-C(O)NR²⁵-(alk)_(b)-,        -(alk)_(a)-C(S)NR²⁵-(alk)_(b)-, -(alk)_(a)-S(O)₂NR²⁵-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(O)-(alk)_(b)-, -(alk)_(a)-NR²⁵C(S)-(alk)_(b)-,        -(alk)_(a)-NR²⁵S(O)₂-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(O)O-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(S)O-(alk)_(b)-,        -(alk)_(a)-OC(O)NR²⁵-(alk)_(b)-,        -(alk)_(a)-OC(S)NR²⁵-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(O)NR²⁵-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(S)NR²⁵-(alk)_(b)-, and        -(alk)_(a)-NR²⁵S(O)₂NR²⁵-(alk)_(b)-;    -   a and b are independently 0 or 1;    -   alk is C₁₋₃ alkylene or C₁₋₃ alkylene substituted with one or        more substituents selected from the group consisting of fluoro,        —OH, —NH₂, lower alkyl, lower alkoxy, lower alkylthio,        mono-alkylamino, di-alkylamino, and —NR⁸R⁹, wherein lower alkyl        or the alkyl chain(s) of lower alkoxy, lower alkylthio,        mono-alkylamino or di-alkylamino are optionally substituted with        one or more substituents selected from the group consisting of        fluoro, —OH, —NH₁₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino and cycloalkylamino, provided,        however, that any substitution of the alkyl chain carbon bound        to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is        fluoro;    -   L₁ is —(CR^(a)R^(b))_(v)— or L, wherein v is 1, 2, or 3;    -   wherein R^(a) and R^(b) at each occurrence are independently        selected from the group consisting of hydrogen, fluoro, —OH,        —NH₂, lower alkyl, lower alkoxy, lower alklylthio,        mono-alkylamino, di-alkylamino, and —NR⁸R⁹, wherein the alkyl        chain(s) of lower alkyl, lower alkoxy, lower alkylthio,        mono-alkylamino, or di-alkylamino are optionally substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino, and cycloalkylamino, provided,        however, that any substitution of the alkyl chain carbon bound        to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is        fluoro; or    -   any two of R^(a) and R^(b) on the same or different carbons        combine to form a 3-7 membered monocyclic cycloalkyl or 5-7        membered monocyclic heterocycloalkyl and any others of R^(a) and        R^(b) are independently selected from the group consisting of        hydrogen, fluoro, —OH, —NH₂, lower alkyl, lower alkoxy, lower        alklylthio, mono-alkylamino, di-alkylamino, and —NR⁸R⁹, wherein        the alkyl chain(s) of lower alkyl, lower alkoxy, lower        alkylthio, mono-alkylamino, or di-alkylamino are optionally        substituted with one or more substituents selected from the        group consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of        mono- or di-alkylamino is fluoro, and wherein the 3-7 membered        monocyclic cycloalkyl or 5-7 membered monocyclic        heterocycloalkyl are optionally substituted with one or more        substituents selected from the group consisting of halogen, —OH,        —NH₂, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino;    -   R⁸ and R⁹ combine with the nitrogen to which they are attached        to form a 5-7 membered heterocycloalkyl optionally substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, and fluoro substituted lower alkylthio;    -   R²⁵ at each occurrence is independently selected from the group        consisting of hydrogen, optionally substituted lower alkyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, and optionally        substituted heteroaryl; and R²⁴ and R²⁶ at each occurrence are        independently selected from the group consisting of hydrogen,        provided, however, that hydrogen is not bound to any of S(O),        S(O)₂, C(O) or C(S) of L or L₁, optionally substituted lower        alkyl, optionally substituted lower alkenyl, provided, however,        that when R²⁴ or R²⁶ is optionally substituted lower alkenyl, no        alkene carbon thereof is bound to N, S, O, S(O), S(O), C(O) or        C(S) of L or L₁, optionally substituted lower alkynyl, provided,        however, that when R²⁴ or R²⁶ is optionally substituted lower        alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O),        S(O)₂, C(O) or C(S) of L or L₁, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, and optionally substituted heteroaryl.

The description above of substituents in Formula I includes descriptionsof each combination of the specified substituents. R², R³, R⁴, R⁵, andR⁶. In some embodiments, at least one of R², R³, R⁴, R⁵ and R⁶ is otherthan hydrogen.

In some embodiments involving compounds of Formula I, R² and R⁶ arehydrogen, or R² and R⁵ are hydrogen, or R² and R⁴ are hydrogen, or R²and R³ are hydrogen, or R³ and R⁶ are hydrogen, or R³ and R⁵ arehydrogen, or R³ and R⁴ are hydrogen, or R⁴ and R⁶ are hydrogen, or R⁴and R⁵ are hydrogen, or R⁵ and R⁶ are hydrogen, wherein thesubstitutions at the other positions are non-hydrogen. In someembodiments, R², R³ and R⁴ are hydrogen, or R², R³ and R⁵ are hydrogen,or R², R³ and R⁶ are hydrogen, or R², R⁴ and R⁵ are hydrogen, or R², R⁴and R⁶ are hydrogen, or R², R⁵ and R⁶ are hydrogen, or R³, R⁴ and R⁵ arehydrogen, or R³, R⁴ and R⁶ are hydrogen, or R³, R⁵ and R⁶ are hydrogen,or R⁴, R⁵ and R⁶ are hydrogen, wherein the substitutions at the otherpositions are non-hydrogen. In some embodiments, the compounds aremono-substituted with non-hydrogen at one of R², R³, R⁴, R⁵ or R⁶ (i.e.hydrogen at the other four positions). In some embodiments, compounds ofFormula I have non-hydrogen substitution at R³; non-hydrogensubstitution at R⁴; non-hydrogen substitution at R⁵; non-hydrogensubstitution at R³ and R⁴; non-hydrogen substitution at R⁴ and R⁵. Insome embodiments, the substitutions as listed are the onlysubstitutions; the substitutions as listed are combined with R² and R⁶as H; the substitutions as listed are combined with substitution at oneother of the substitution positions shown in Formula I. The compounds ofFormula I, and all sub-embodiments detailed herein, may be used to treata subject suffering from or at risk for any of the protein kinasemediated diseases or conditions contemplated herein.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ia:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y³ is abond, —CR^(a)R^(b)—, -A-Ar-L₁-, or L, and Y⁵ is a bond, —CR^(a)R^(b)—,or L, and each R²⁷ is independently halogen, provided that Y³ or Y⁵ is abond, or R²⁶, provided, however, that neither of Y³R²⁷ and Y⁵R²⁷ arehydrogen, wherein R^(a), R^(b), L, L₁, A, Ar and R²⁶ are as defined withreference to Formula I.

In some embodiments of compounds of Formula Ia, Y³ and Y⁵ are bonds. Insome embodiments, Y³ and Y⁵ are independently —CR^(a)R^(b)— or L. Insome embodiments, Y³ and Y⁵ are independently L. In some embodiments, Y³and Y⁵ are independently —CR^(a)R^(b)—. In some embodiments, Y³ is abond, and Y⁵ is —CR^(a)R^(b)— or L. In some embodiments, Y³ is a bond,and Y⁵ is L. In some embodiments, Y³ is a bond, and Y⁵ is —CR^(a)R^(b)—.In some embodiments, Y⁵ is a bond, and Y³ is —CR^(a)R^(b)— or L. In someembodiments, Y⁵ is a bond, and Y³ is L. In some embodiments, Y⁵ is abond, and Y³ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Ia, each R⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y³or Y⁵ is a bond. In some embodiments, Y⁵ is a bond, —CR^(a)R^(b)—, or L,Y³ is —CR^(a)R^(b)—, —O—, —S—, —NR²⁵—, —C(O)—, —C(S)—, —S(O)—, or—S(O)₂—, wherein R²⁵ is as defined for Formula I, and each R²⁷ isindependently R²⁶ or Y⁵R²⁷ is halogen; in further embodiments, Y³ is—CR^(a)R^(b)— or —C(O)—; in further embodiments, —CR^(a)R^(b)— is —CH₂—.In some embodiments, Y⁵ is a bond, —CR^(a)R^(b)—, or L, R²⁷ bound to Y⁵is R²⁶ or Y⁵R²⁷ is halogen, Y³ is —CR^(a)R^(b)— or —C(O)—, and R²⁷ boundto Y³ is optionally substituted aryl or optionally substitutedheteroaryl.

In some embodiments of any of the above embodiments of compounds ofFormula Ia, Y³R²⁷ is -A-Ar-L₁-R²⁴, wherein A, Ar, and L₁ are as definedfor Formula I, and R²⁴ is substituted methyl, optionally substitutedC₂₋₆ alkyl, optionally substituted lower alkenyl, provided, however,that when R²⁴ is optionally substituted lower alkenyl, no alkene carbonthereof is bound to N, S, O, S(O), S(O)₃, C(O) or C(S) of L₁, optionallysubstituted lower alkynyl, provided, however, that when R²⁴ is or C(S)of L₁, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, provided, however, that -A-Ar-L₁-R²⁴ is not

wherein

indicates the point of attachment to the 3 position of the azaindolering; in further embodiments, R⁴ is optionally substituted C₂, alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or substituted methyl, wherein methyl is substituted withoptionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; in further embodiments, when Ar is optionally substitutedheteroarylene, the heteroarylene ring is not a five or six membered ringhaving the structure

wherein

indicates the point of attachment to A and

indicates the point of attachment to L₁, and wherein the indicated N iseither ═N— or —N═, and wherein each Q is independently a heteroaryl ringatom that may be optionally substituted. The term “heteroaryl ring atom”refers to any atom that can be part of a heteroaryl ring structure(i.e., C, N, O, or S).

In some embodiments of any of the above embodiments of compounds ofFormula Ia, Y³ and Y⁵ are independently —O—, —S—, —CR^(a)R^(b)—, —NR²⁵—,—C(O)—, —C(S)—, —S(O)—, or —S(O)₂—, where R^(a), R^(b) and R²⁵ are asdefined in Formula I, and each R²⁷ is independently optionallysubstituted lower alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; in further embodiments, Y⁵ is —O—, —NR²⁵—, or—S(O)₂—, preferably wherein R²⁵ is hydrogen or lower alkyl, and R²⁷bound to Y³ is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, preferably optionally substituted aryl, or optionallysubstituted heteroaryl; in further embodiments, Y³ is —CR^(a)R^(b)—, or—C(O)—, preferably —CH₂— or —C(O)—, Y⁵ is —O—, —NR²⁵—, or —S(O)₂—,preferably —NR²⁵—, wherein R²⁵ is hydrogen or lower alkyl, and each R²⁷is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, preferably optionally substituted aryl, or optionallysubstituted heteroaryl, provided, however, that Y³R²⁷ is not

wherein

indicates the bond to the 3 position of the 7-azaindole ring, and Y⁵R²⁷is not

wherein

indicates the bond to the 5 position of the 7-azaindole ring, i.e. thecompound is not(3-hydroxy-phenyl)-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone;in further embodiments, when R²⁷ bound to Y³ is optionally substitutedheteroaryl, the heteroaryl ring is not a five or six membered ringhaving the structure

wherein

indicates the point of attachment to Y³, and wherein the indicated N iseither ═N— or —N═, and wherein each Q is independently a heteroaryl ringatom that may be appropriately optionally substituted and wherein R²⁰⁰is other than hydrogen. The term “other than hydrogen” and like termsrefer to substituents contemplated herein which are not hydrogen. Forexample without limitation, if substituent R^(ex) were defined asselected from the group consisting of hydrogen and optionallysubstituted lower alkyl, then the phrase “R^(ex) is other than hydrogen”would contemplate only optionally substituted lower alkyl, i.e. alloptions of the substituent, excluding hydrogen.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ib:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y³ and Y⁴are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y³ or Y⁴ is a bond, or R²⁶,provided, however, that neither of Y³R²⁷ and Y⁴R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Ib, Y³ and Y⁴ are bonds. Insome embodiments, Y³ and Y⁴ are independently —CR^(a)R^(b)— or L. Insome embodiments, Y³ and Y⁴ are independently L. In some embodiments, Y³and Y⁴ are independently —CR^(a)R^(b)—. In some embodiments, Y³ is abond and Y⁴ is —CR^(a)R^(b)— or L. In some embodiments, Y³ is a bond andY⁴ is L. In some embodiments, Y³ is a bond and Y⁴ is —CR^(a)R^(b)—. Insome embodiments, Y⁴ is a bond, and Y³ is —CR^(a)R^(b)— or L. In someembodiments, Y⁴ is a bond and Y³ is L. In some embodiments, Y⁴ is a bondand Y³ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Ib, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y³or Y⁴ is a bond. In some embodiments, Y⁴ is a bond, —CR^(a)R^(b)—, or L,Y³ is —CR^(a)R^(b)—, —O—, —S—, —NR²⁵—, —C(O)—, —C(S)—, —S(O)—, or—S(O)₂—, wherein R²⁵ is as defined for Formula I, and R²⁷ isindependently R²⁶ or Y⁴R²⁷ is halogen; in further embodiments, Y³ is—CR^(a)R^(b)— or —C(O)—; in further embodiments, —CR^(a)R^(b)— is —CH₂—.In some embodiments, Y⁴ is a bond, —CR^(a)R^(b)—, or L, R²⁷ bound to Y⁴is R²⁶ or Y⁴R²⁷ is halogen, Y³ is —CR^(a)R^(b)— or —C(O)—, and R²⁷ boundto Y³ is optionally substituted aryl or optionally substitutedheteroaryl.

In some embodiments of any of the above embodiments of compounds ofFormula Ib. Y³ and Y⁴ are independently —O—, —S—, —CR^(a)R^(b)—, —NR²⁵—,—C(O)—, —C(S)—, —S(O)—, or —S(O)₂—, where R^(a), R^(b) and R²⁵ are asdefined in Formula I, and each R²⁷ is independently optionallysubstituted lower alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; in a further embodiment Y⁴ is —O—, —NR²⁵—, or—S(O)—, preferably wherein R²⁵ is hydrogen or lower alkyl, and R²⁷ boundto Y³ is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, preferably optionally substituted aryl, or optionallysubstituted heteroaryl; in a further embodiment Y³ is —CR^(a)R^(b)—, or—C(O)—, preferably —CH₂— or —C(O)—, Y⁴ is —O—, —NR²⁵—, or —S(O)₂—,preferably —NR²⁵—, wherein R²⁵ is hydrogen or lower alkyl, and each R²⁷is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, preferably optionally substituted aryl, or optionallysubstituted heteroaryl.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ic:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y³ and Y⁶are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y³ or Y⁶ is a bond, or R²⁶,provided, however, that neither of Y³R²⁷ and Y⁶R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Ic, Y³ and Y⁶ are bonds. Insome embodiments, Y³ and Y⁶ are independently —CR^(a)R^(b)— or L. Insome embodiments, Y³ and Y⁶ are independently L. In some embodiments, Y³and Y⁶ are independently —CR^(a)R^(b)—. In some embodiments, Y³ is abond, and Y⁶ is —CR^(a)R^(b)— or L. In some embodiments, Y³ is a bond,and Y⁶ is L. In some embodiments, Y³ is a bond, and Y⁶ is —CR^(a)R^(b)—.In some embodiments, Y⁶ is a bond, and Y³ is —CR^(a)R^(b)— or L. In someembodiments, Y⁶ is a bond, and Y³ is L. In some embodiments, Y⁶ is abond, and Y³ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Ic, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y³or Y⁶ is a bond.

In some embodiments of any of the above embodiments of compounds ofFormula Ia, Y³ and Y⁶ are independently —O—, —S—, —CR^(a)R^(b)—, —NR²⁵—,—C(O)—, —C(S)—, —S(O)—, or —S(O)₂—, where R^(a), R^(b) and R²⁵ are asdefined in Formula I, and each R²⁷ is independently optionallysubstituted lower alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; in further embodiments, Y⁶ is —O—, —NR²⁵—, or—S(O)₂—, preferably wherein R²⁵ is hydrogen or lower alkyl, and R²⁷bound to Y³ is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, preferably optionally substituted aryl, or optionallysubstituted heteroaryl; in further embodiments, Y³ is —CR^(a)R^(b)—, or—C(O)—, preferably —CH₂— or —C(O)—, Y⁶ is —O—, —NR²⁵—, or —S(O)₂—,preferably —NR²⁵—, wherein R²⁵ is hydrogen or lower alkyl, and each R²⁷is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, preferably optionally substituted aryl, or optionallysubstituted heteroaryl.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Id:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y³ and Y²are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y³ or Y² is a bond, or R²⁶,provided, however, that neither of Y²R²⁷ and Y³R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Id, Y³ and Y² are bonds. Insome embodiments, Y³ and Y² are independently —CR^(a)R^(b)— or L. Insome embodiments, Y³ and Y² are independently L. In some embodiments, Y³and Y² are independently —CR^(a)R^(b)—. In some embodiments, Y³ is abond, and Y² is —CR^(a)R^(b)— or L. In some embodiments, Y³ is a bond,and Y² is L. In some embodiments, Y³ is a bond, and Y² is —CR^(a)R^(b)—.In some embodiments, Y² is a bond, and Y³ is —CR^(a)R^(b)— or L. In someembodiments, Y² is a bond, and Y³ is L. In some embodiments, Y² is abond, and Y³ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Id, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y³or Y² is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ie:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y⁴ and Y²are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y⁴ or Y² is a bond, or R²⁶,provided, however, that neither of Y²R²⁷ and Y⁴R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Ie, Y⁴ and Y² are bonds. Insome embodiments, Y⁴ and Y² are independently —CR^(a)R^(b)— or L. Insome embodiments, Y⁴ and Y² are independently L. In some embodiments, Y⁴and Y² are independently —CR^(a)R^(b)—. In some embodiments, Y⁴ is abond, and Y² is —CR^(a)R^(b)— or L. In some embodiments, Y⁴ is a bond,and Y² is L. In some embodiments, Y⁴ is a bond, and Y² is —CR^(a)R^(b)—.In some embodiments, Y² is a bond and Y⁴ is —CR^(a)R^(b)— or L. In someembodiments, Y² is a bond, and Y⁴ is L. In some embodiments, Y² is abond, and Y⁴ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Id, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y⁴or Y² is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula If:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y⁵ and Y²are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y⁵ or Y² is a bond, or R²⁶,provided, however, that neither of Y²R²⁷ and Y⁵R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula If, Y⁵ and Y² are bonds. Insome embodiments, Y⁵ and Y² are independently —CR^(a)R^(b)— or L. Insome embodiments, Y⁵ and Y² are independently L. In some embodiments, Y⁵and Y² are independently —CR^(a)R^(b)—. In some embodiments, Y⁵ is abond, and Y² is —CR^(a)R^(b)— or L. In some embodiments, Y⁵ is a bond,and Y² is L. In some embodiments, Y⁵ is a bond, and Y² is —CR^(a)R^(b)—.In some embodiments, Y² is a bond, and Y⁵ is —CR^(a)R^(b)— or L. In someembodiments, Y² is a bond, and Y² is L. In some embodiments, Y² is abond, and Y⁵ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula If, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y⁵or Y² is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ig:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y⁶ and Y²are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y⁶ or Y² is a bond, or R²⁶,provided, however, that neither of Y²R²⁷ and Y⁶R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Ig, Y⁶ and Y² are bonds. Insome embodiments, Y⁶ and Y² are independently —CR^(a)R^(b)— or L. Insome embodiments, Y⁶ and Y² are independently L. In some embodiments, Y⁶and Y² are independently —CR^(a)R^(b)—. In some embodiments, Y⁶ is abond, and Y⁷ is —CR^(a)R^(b)— or L. In some embodiments, Y⁶ is a bond,and Y² is L. In some embodiments, Y⁶ is a bond, and Y² is —CR^(a)R^(b)—.In some embodiments, Y² is a bond, and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, Y² is a bond, and Y⁶ is L. In some embodiments, Y² is abond, and Y⁶ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Ig, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y⁶or Y² is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ih:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y⁶ and Y⁴are in independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y⁶ or Y⁴ is a bond, or R²⁶,provided, however, that neither of Y⁴R²⁷ and Y⁶R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Ih, Y⁶ and Y⁴ are bonds. Insome embodiments, Y⁶ and Y⁴ are independently —CR^(a)R^(b)— or L. Insome embodiments, Y⁶ and Y⁴ are independently L. In some embodiments, Y⁶and Y⁴ are independently —CR^(a)R^(b)—. In some embodiments, Y⁶ is abond, and Y⁴ is —CR^(a)R^(b)— or L. In some embodiments, Y⁶ is a bond,and Y⁴ is L.

In some embodiments, Y⁶ is a bond, and Y⁴ is —CR^(a)R^(b)—. In someembodiments, Y⁴ is a bond and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, Y⁴ is a bond, and Y⁶ is L. In some embodiments, Y⁴ is abond, and Y⁶ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Ih, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y⁶or Y⁴ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula II:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y⁶ and Y⁵are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y⁶ or Y⁵ is a bond, or R²⁶,provided, however, that neither of Y⁵R² and Y⁶R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Ii, Y⁶ and Y⁵ are bonds. Insome embodiments, Y⁶ and Y⁵ are independently —CR^(a)R^(b)— or L. Insome embodiments, Y⁶ and Y⁵ are independently L. In some embodiments, Y⁶and Y⁵ are independently —CR^(a)R^(b)—. In some embodiments, Y⁶ is abond, and Y⁵ is —CR^(a)R^(b)— or L. In some embodiments, Y⁶ is a bond,and Y⁵ is L. In some embodiments, Y⁶ is a bond, and Y⁵ is —CR^(a)R^(b)—.In some embodiments, Y⁵ is a bond, and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, Y⁵ is a bond, and Y⁶ is L. In some embodiments, Y⁵ is abond, and Y⁶ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Ii, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y⁶or Y⁵ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ij:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y⁴ and Y⁵are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y⁴ or Y⁵ is a bond, or R²⁶,provided, however, that neither of Y⁴R²⁷ and Y⁵R²⁷ are hydrogen, whereinR^(a), R^(b), L and R²⁶ are as defined with reference to Formula I.

In some embodiments of compounds of Formula Ij, Y⁴ and Y⁵ are bonds. Insome embodiments, Y⁴ and Y⁵ are independently —CR^(a)R^(b)— or L. Insome embodiments, Y⁴ and Y⁵ are independently L. In some embodiments, Y⁴and Y⁵ are independently —CR^(a)R^(b)—. In some embodiments, Y⁴ is abond, and Y⁵ is —CR^(a)R^(b)— or L. In some embodiments, Y⁴ is a bond,and Y⁵ is L. In some embodiments, Y⁴ is a bond, and Y⁵ is —CR^(a)R^(b)—.In some embodiments, Y⁵ is a bond, and Y⁴ is —CR^(a)R^(b)— or L. In someembodiments, Y⁵ is a bond, and Y⁴ is L. In some embodiments, Y⁵ is abond, and Y⁴ is —CR^(a)R^(b)—.

In some embodiments of any of the above embodiments of compounds ofFormula Ij, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y⁴or Y⁵ is a bond.

In some embodiments, compounds of Formula I have the structure accordingto the following sub-generic structure Formula Ik:

all salts, prodrugs, tautomers, and isomers thereof, wherein R²⁶ is asdefined in Formula I, and Y is selected from the group consisting of abond, —CR^(a)R^(b)— and L, where R^(a), R^(b) and L are as defined withreference to Formula I, provided that YR²⁶ is not hydrogen.

In some embodiments of compounds of Formula Ik, Y is-(alk)_(a)-S-(alk)_(b)-, -(alk)_(a)-O-(alk)_(b)-,-(alk)_(a)-OC(O)-(alk)_(b)-, -(alk)_(a)-C(O)O-(alk)_(b)-,-(alk)_(a)-OC(S)-(alk)_(b)-, -(alk)_(a)-C(S)O-(alk)_(b)-,-(alk)_(a)-C(O)-(alk)_(b)-, -(alk)_(a)-C(S)-(alk)_(b)-,-(alk)_(a)-C(O)NR²⁵-(alk)_(b)-, -(alk)_(a)-OC(O)NR²⁵-(alk)_(b)-,-(alk)_(a)-OC(S)NR²⁵-(alk)_(b)-, -(alk)_(a)-C(S)NR²⁵-(alk)_(b)-,-(alk)_(a)-S(O)-(alk)_(b)-, -(alk)_(a)-S(O)₂-(alk)_(b)-,-(alk)_(a)-S(O)₂NR²⁵-(alk)_(b)-, -(alk)_(a)-NR²⁵-(alk)_(b)-,-(alk)_(a)-NR²⁵C(O)-(alk)_(b)-, -(alk)_(a)-NR²⁵C(S)-(alk)_(b)-,-(alk)_(a)-NR²⁵C(O)NR²⁵-(alk)_(b)-, -(alk)_(a)-NR²⁵C(S)NR²⁵-(alk)_(b)-,-(alk)-NR²⁵C(O)O-(alk)_(b)-, -(alk)_(a)-NR²⁵C(S)O-(alk)_(b)-,-(alk)_(a)-NR²⁵S(O)₂-(alk)_(b)-, or -(alk)_(a)-NR²⁵S(O)₂NR²⁵-(alk)_(b)-,wherein alk, a, b, and R²⁵ are as defined for Formula I.

In some embodiments of compounds of Formula Ik, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —C(O)O-(alk)_(b)-, —OC(S)-(alk)_(b)-,—C(S)O-(alk)_(b)-, —C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-,—C(O)NR²⁵-(alk)_(b)-, —OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-,—C(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-,S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In some embodiments of compounds of Formula Ik, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —OC(S)-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-,—S(O)₂-(alk)_(b)-, S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-,—NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In some embodiments of compounds of Formula Ik, R²⁶ is optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments. Y is —O—, —S—, —NR²⁵—, —C(O)—, —C(S)—, —S(O)—, or—S(O)₂— and R²⁶ is optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl. In some embodiments, Y is —NR²⁵—, preferablywherein R²⁵ is hydrogen or lower alkyl, preferably wherein Y is —NH—; infurther embodiments, R²⁶ is optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; in further embodiments, lower alkyl is substituted withoptionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; in further embodiments, heteroaryl is monocyclic. In someembodiments, Y is —NH—; in further embodiments, R²⁶ is substitutedphenyl or optionally substituted heteroaryl, provided that heteroaryl ismonocyclic.

In some embodiments of any of the above embodiments of compounds ofFormula Ik, YR²⁶ is not optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C≡CCH₂N(CH₃)₂, —C(O)H, —CH₂N(CH₃)₂, —C(O)OCH₃,—CH₂OH, —OH, —OCH₃, —NHCH₂CH═CH₂, —NHCH₃, —NHCH₂CH₃, —NHphenyl,

wherein

indicates the bond attached to the 5-position of the 7-azaindole ring;and when Y is —O— or —NR²⁵—, then R²⁶ is not

which is optionally substituted, wherein

indicates the bond attached to Y; and when Y is —O—, then R²⁶ is not

which is optionally substituted, wherein

indicates the bond attached Y.

In some embodiments, compounds of Formula I have the structure accordingto the following sub-generic structure Formula Im:

all salts, prodrugs, tautomers, and isomers thereof, wherein R²⁶ and Yare as defined for Formula Ik.

In some embodiments of compounds of Formula Im, Y is —OC(O)-(alk)_(b)-,—C(O)O-(alk)_(b)-, —OC(S)-(alk)_(b)-, —C(S)O-(alk)_(b)-,—C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-, —C(O)NR²⁵-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —C(S)NR²⁵-(alk)_(b)-,—S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-, S(O)₂NR²⁵-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In other embodiments of compounds of Formula Im, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —C(O)O-(alk)_(b)-, —OC(S)-(alk)_(b)-,—C(S)O-(alk)_(b)-, —C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-,—C(O)₂NR²⁵-(alk)_(b)-, —OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-,—C(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-,—S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵— (alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In other embodiments of compounds of Formula Im, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —OC(S)-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —S(O)₂-(alk)_(b)-,—S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In some embodiments of compounds of Formula Im, R²⁶ is optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments, Y is —O—, —S—, —NR²⁵—, —C(O)—, —C(S)—, —S(O)—, or—S(O)₂— and R²⁶ is optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl. In some embodiments, Y is —NR²⁵—, preferablywherein R²⁵ is hydrogen or lower alkyl, preferably wherein Y is —NH—; infurther embodiments, R²⁶ is optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; in further embodiments, lower alkyl is substituted withoptionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; in further embodiments, heteroaryl is monocyclic.

In some embodiments of any of the above embodiments of compounds ofFormula Im, when Y is —CH₂NH—, then R²⁶ is not optionally substitutedthiophene or optionally substituted pyridine; when Y is —O— or —NH—,then R²⁶ is not optionally substituted bicyclic heteroaryl; when Y is—O—, then R²⁶ is not optionally substituted phenyl; when Y is —NH— or—N(CH₃)— and R²⁶ is substituted phenyl, the phenyl is not substituted byhalogen ortho to Y and optionally substituted amine para to Y, Y is not—NH—C(O)— or —C(O)—NH—, and YR²⁶ is not optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted —CH═CH₂, —C(O)OH, —C(O)OCH₃, —C(O)OtBu, —OH, —OCH₃,—NHCH₂CH—CH₂, —N(CH₃)₂, —NH₂, —NHCH₂C(O)OCH₂CH₃, —N(CH₃)phenyl,

wherein

indicates the bond attached to the 4-position of the 7-azaindole ring.

In some embodiments, compounds of Formula I have the structure accordingto the following sub-generic structure Formula In:

all salts, prodrugs, tautomers, and isomers thereof, wherein R²⁶ and Yare as defined for Formula Ik

In other embodiments of compounds of Formula In, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —C(O)O-(alk)_(b)-, —OC(S)-(alk)_(b)-,—C(S)O-(alk)_(b)-, —C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-,—C(O)NR²⁵-(alk)_(b)-, —OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-,—C(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-,—S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In other embodiments of compounds of Formula In, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —OC(S)-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-,—S(O)₂-(alk)_(b)-, —S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-,—NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In some embodiments of compounds of Formula In, R²⁶ is optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments, Y is —NR²⁵—, preferably wherein R²⁵ is hydrogen orlower alkyl, preferably wherein Y is —NH—; in further embodiments, R²⁶is optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; in furtherembodiments, lower alkyl is substituted with optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl.

In some embodiments of any of the above embodiments of compounds ofFormula In, compounds are excluded where Y is —O— and R²⁶ is optionallysubstituted

wherein

indicates the bond attached to Y; where YR²⁶ is —NH₂, —CH₃,—OC(O)phenyl,

wherein

indicates the bond attached to the 6-position of the 7-azaindole ring.

In some embodiments, compounds of Formula I have the structure accordingto the following sub-generic structure Formula Io:

all salts, prodrugs, tautomers, and isomers thereof, wherein R²⁶ and Yare as defined for Formula Ik.

In other embodiments of compounds of Formula Io, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —C(O)O-(alk)_(b)-, —OC(S)-(alk)_(b)-,—C(S)O-(alk)_(b)-, —C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-,—C(O)NR²⁵-(alk)_(b)-, —OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-,—C(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-,—S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In other embodiments of compounds of Formula Io, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —OC(S)-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-,—S(O)₂-(alk)_(b)-, —S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-,—NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In some embodiments of compounds of Formula Io, R²⁶ is optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments, Y is —NR²⁵—, preferably wherein R²⁵ is hydrogen orlower alkyl, preferably wherein Y is —NH—; in further embodiments, R²⁶is optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; in furtherembodiments, lower alkyl is substituted with optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl.

In some embodiments of any of the above embodiments of compounds ofFormula Io, compounds are excluded when —YR²⁶ is optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —CH₂NR′R″, whereinNR′R″ is optionally substituted heterocycloalkyl or optionallysubstituted heteroaryl, —C(O)NR′R″, wherein NR′R″ is optionallysubstituted heterocycloalkyl or optionally substituted heteroaryl, or R′is H and R″ is optionally substituted cycloalkyl, optionally substitutedaryl or optionally substituted heteroaryl, optionally substituted—CH—CH₂, —CH₃, —CH₂CH₂NHCH₃, —CH₂CH(NH₂)C(O)OH, —CH₂CH(NH₂)C(O)OCH₃,—CH₂CH(C(O)OH)NHCH₃, —C(O)C(O)OCH₃, —CH₂C(O)OCH₂CH₃, —CH₂C(O)NH₂,—CH₂CN, —NH₂, —N(CH₃)₂, —SCH₃, —N═C(CH₃)NHOAc, —C(O)CCl₃, —C(O)OCH₃,—C(O)CH₂Br, —C(O)NH₂, —C(S)NH₂, —CH₂NH-thiophene, wherein thiophene isoptionally substituted,

wherein the phenyl ring is optionally substituted,

wherein the ring is optionally substituted at D₁, D₂ and D₃,

wherein the ring is optionally substituted at D₁, D₂ and D₃,

when R is H, F, Cl, CH₃, CF₃ or OCH₃,

when R is H, 4-F, 4-CF₃ or 3-F, or

when R′ is OCH₃ or CH₃ and R is CF₃, or when R is CH₃ and R is Cl,wherein

indicates the bond attached to the 3-position of the 7-azaindole ring.

In some embodiments, compounds of Formula I have the structure accordingto the following sub-generic structure Formula Ip:

all salts, prodrugs, tautomers, and isomers thereof, wherein R²⁶ and Yare as defined for Formula Ik.

In other embodiments of compounds of Formula Ip, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —C(O)O-(alk)_(b)-, —OC(S)-(alk)_(b)-,—C(S)O-(alk)_(b)-, —C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-,—C(O)NR²⁵-(alk)_(b)-, —OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-,—C(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-,—S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²″-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In other embodiments of compounds of Formula Ip, Y is —S-(alk)_(b)-,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —OC(S)-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —S(O)-(alk)_(b)-,—S(O)₂-(alk)_(b)-, —S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵-(alk)_(b)-,—NR²⁵C(O)-(alk)_(b), —NR²⁵C(S)-(alk)_(b), —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein alk, b andR²⁵ are as defined for Formula I.

In some embodiments of compounds of Formula Ip, R²⁶ is optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments, Y is —NR²⁵—, preferably wherein R²⁵ is hydrogen orlower alkyl, preferably wherein Y is —NH—; in further embodiments, R²⁶is optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; in furtherembodiments, lower alkyl is substituted with optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl.

In some embodiments of any of the above embodiments of compounds ofFormula Ip above, compounds are excluded when YR²⁶ is —CH₃, optionallysubstituted aryl, optionally substituted cycloalkyl

wherein

indicates the bond attached to the 2-position of the 7-azaindole ring.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Iq:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y² Y³ andY⁴ are independently a bond, —CR^(a)R^(b)— or L, and each R²⁷ isindependently halogen, provided that Y², Y³ or Y⁴ is a bond, or R²⁶provided, however, that none of Y²R²⁷, Y³R²⁷, and Y⁴R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Iq, Y², Y³ and Y⁴ are bonds.In some embodiments, Y², Y³ and Y⁴ are independently —CR^(a)R^(b)— or L.In some embodiments, Y², Y³ and Y⁴ are independently L. In someembodiments, one of Y², Y³ and Y⁴ is a bond, and the others areindependently —CR^(a)R^(b)— or L. In some embodiments, one of Y², Y³ andY⁴ is a bond, and the others are independently L. In some embodiments,two of Y², Y³ and Y⁴ are bonds, and the other is —CR^(a)R^(b)— or L. Insome embodiments, two of Y², Y³ and Y⁴ are bonds and the other is L.

In some embodiments of any of the above embodiments of compounds ofFormula Iq, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y²,Y³ or Y⁴ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ir:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y² Y³ andY⁵ are independently a bond, —CR^(a)R^(b)— or L, and each R²⁷ isindependently halogen, provided that Y², Y² or Y³ is a bond, or R²⁶,provided, however, that none of Y²R²⁷, Y³R²⁷, and Y⁵R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Ir, Y², Y³ and Y⁵ are bonds.In some embodiments, Y², Y³ and Y⁵ are independently —CR^(a)R^(b)— or L.In some embodiments, Y², Y³ and Y⁵ are independently L. In someembodiments, any one of Y², Y³ and Y⁵ is a bond, and the remaining ofY², Y³ and Y⁵ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y², Y³ and Y⁵ is a bond, and the remaining of Y², Y³ and Y⁵are independently L. In some embodiments, any two of Y² Y³ and Y⁵ arebonds, and the remaining of Y², Y³ and Y⁵ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y², Y³ and Y⁵ are bonds, and the remaining ofY², Y³ and Y⁵ is L.

In some embodiments of any of the above embodiments of compounds ofFormula Ir, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y²,Y³ or Y⁵ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Is:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y² Y³ andY⁶ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y², Y³ or Y⁶ is a bond, or R²⁶,provided, however, that none of Y²R²⁷, Y³R²⁷, and Y⁶R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Is, Y², Y³ and Y⁶ are bonds.In some embodiments, Y², Y³ and Y⁶ are independently —CR^(a)R^(b)— or L.In some embodiments, Y², Y³ and Y⁶ are independently L. In someembodiments, any one of Y², Y³ and Y⁶ is a bond, and the remaining ofY², Y³ and Y⁶ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y², Y³ and Y⁶ is a bond, and the remaining of Y², Y³ and Y⁶are independently L. In some embodiments, any two of Y², Y³ and Y⁶ arebonds, and the remaining of Y², Y³ and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y², Y³ and Y⁶ are bonds, and the remaining ofY², Y³ and Y⁶ is L.

In some embodiments of any of the above embodiments of compounds ofFormula Is, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y²,Y³ or Y⁶ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula It:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y² Y⁴ andY⁵ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y², Y⁴ or Y⁵ is a bond, or R²⁶,provided, however, that none of Y²R²⁷, Y⁴R²⁷, and Y⁵R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula It, Y², Y⁴ and Y⁵ are bonds.In some embodiments, Y², Y⁴ and Y⁵ are independently —CR^(a)R^(b)— or L.In some embodiments, Y², Y⁴ and Y⁵ are independently L. In someembodiments, any one of Y², Y⁴ and Y⁵ is a bond, and the remaining ofY², Y⁴ and Y⁵ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y², Y⁴ and Y⁵ is a bond, and the remaining of Y², Y⁴ and Y⁵are independently L. In some embodiments, any two of Y², Y⁴ and Y⁵ arebonds, and the remaining of Y², Y⁴ and Y⁵ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y², Y⁴ and Y⁵ are bonds, and the remaining ofY². Y⁴ and Y⁵ is L.

In some embodiments of any of the above embodiments of compounds ofFormula It, each R² is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R¹⁷ is halogen, provided that Y²,Y⁴ or Y⁵ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Iu:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y² Y⁴ andY⁶ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y², Y⁴ or Y⁶ is a bond, or R²⁶provided, however, that none of Y²R²⁷, Y⁴R²⁷, and Y⁶R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

some embodiments of compounds of Formula Iu, Y², Y⁴ and Y⁶ are bonds. Insome embodiments, Y², Y⁴ and Y⁶ are independently —CR^(a)R^(b)— or L. Insome embodiments, Y², Y⁴ and Y⁶ are independently L. In someembodiments, any one of Y², Y⁴ and Y⁶ is a bond, and the remaining ofY², Y⁴ and Y⁶ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y², Y⁴ and Y⁶ is a bond, and the remaining of Y², Y⁴ and Y⁶are independently L. In some embodiments, any two of Y², Y⁴ and Y^(b)are bonds, and the remaining of Y², Y⁴ and Y⁶ is —CR^(a)R^(b)— or L. Insome embodiments, any two of Y², Y⁴ and Y⁶ are bonds, and the remainingof Y², Y⁴ and Y⁶ is L.

In some embodiments of any of the above embodiments of compounds ofFormula Iu, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y²,Y⁴ or Y⁶ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Iv:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y² Y⁵ andY⁶ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y², Y⁵ or Y⁶ is a bond, or R²⁶,provided, however, that none of Y²R²⁷, Y⁵R²⁷, and Y⁶R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Iv, Y², Y⁵ and Y⁶ are bonds.In some embodiments, Y², Y⁵ and Y⁶ are independently —CR^(a)R^(b)— or L.In some embodiments, Y², Y⁵ and Y⁶ are independently L. In someembodiments, any one of Y², Y⁵ and Y⁶ is a bond, and the remaining ofY², Y⁵ and Y⁶ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y², Y⁵ and Y⁶ is a bond, and the remaining of Y², Y⁵ and Y⁶are independently L. In some embodiments, any two of Y², Y⁵ and Y⁶ arebonds, and the remaining of Y², Y⁵ and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y², Y⁵ and Y⁶ are bonds, and the remaining ofY², Y⁵ and Y⁶ is L.

In some embodiments of any of the above embodiments of compounds ofFormula Iv, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y²,Y or Y⁶ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Iw:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y³ Y⁴ andY⁵ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y³, Y⁴ or Y⁵ is a bond, or R²⁶,provided, however, that none of Y³R²⁷, Y⁴R²⁷, and Y⁵R¹⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Iw, Y³, Y⁴ and Y⁵ are bonds.In some embodiments, Y³, Y⁴ and Y⁵ are independently —CR^(a)R^(b)— or L.In some embodiments, Y³, Y⁴ and Y⁵ are independently L. In someembodiments, any one of Y³, Y⁴ and Y⁵ is a bond, and the remaining ofY³, Y⁴ and Y⁵ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y³, Y⁴ and Y⁵ is a bond, and the remaining of Y³, Y⁴ and Y⁵are independently L. In some embodiments, any two of Y³, Y⁴ and Y⁵ arebonds, and the remaining of Y³, Y⁴ and Y⁵ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y³, Y⁴ and Y^(s) are bonds, and the remaining ofY³, Y⁴ and Y⁵ is L.

In some embodiments of any of the above embodiments of compounds ofFormula Iw, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y³,Y⁴ or Y⁵ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Ix:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y³ Y⁴ andY⁶ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y³, Y⁴ or Y⁶ is a bond, or R²⁶,provided, however, that none of Y²R²⁷, Y⁴R²⁷, and Y⁶R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Ix, Y³, Y⁴ and Y⁶ are bonds.In some embodiments, Y³, Y⁴ and Y⁶ are independently —CR^(a)R^(b)— or L.In some embodiments, Y³, Y⁴ and Y⁶ are independently L. In someembodiments, any one of Y³, Y⁴ and Y⁶ is a bond, and the remaining ofY³, Y⁴ and Y⁶ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y³, Y⁴ and Y⁶ is a bond, and the remaining of Y³, Y⁴ and Y⁶are independently L. In some embodiments, any two of Y³, Y⁴ and Y⁶ arebonds, and the remaining of Y³, Y⁴ and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y³, Y⁴ and Y⁶ are bonds, and the remaining ofY³, Y⁴ and Y⁶ is L.

In some embodiments of any of the above embodiments of compounds ofFormula Ix, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R¹⁷ is halogen, provided that Y³,Y⁴ or Y⁶ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Iy:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y³ Y⁵ andY⁶ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y³, Y⁵ or Y is a bond, or R²⁶,provided, however, that none of Y³R²⁷, Y⁵R²⁷, and Y⁶R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Iy, Y³, Y⁵ and Y⁶ are bonds.In some embodiments, Y³, Y⁵ and Y⁶ are independently —CR^(a)R^(b)— or L.In some embodiments, Y³, Y⁵ and Y⁶ are independently L. In someembodiments, any one of Y³, Y⁵ and Y⁶ is a bond, and the remaining ofY³, Y⁵ and Y⁶ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y³, Y⁵ and Y⁶ is a bond, and the remaining of Y³, Y⁵ and Y⁶are independently L. In some embodiments, any two of Y³, Y⁵ and Y⁶ arebonds, and the remaining of Y³, Y⁵ and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y³, Y⁵ and Y⁶ are bonds, and the remaining ofY³, Y⁵ and Y⁶ is L.

In some embodiments of any of the above embodiments of compounds ofFormula Iy, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y³,Y⁵ or Y⁶ is a bond.

In some embodiments, the compound of Formula I has a structure accordingto the following sub-generic structure Formula Iz:

all salts, prodrugs, tautomers, and isomers thereof, wherein Y⁴ Y⁵ andY⁶ are independently a bond, —CR^(a)R^(b)—, or L, and each R²⁷ isindependently halogen, provided that Y⁴, Y⁵ or Y⁶ is a bond, or R²⁶,provided, however, that none of Y⁴R²⁷, Y⁵R²⁷, and Y⁶R²⁷ are hydrogen,wherein R^(a), R^(b), L and R²⁶ are as defined with reference to FormulaI.

In some embodiments of compounds of Formula Iz, Y⁴, Y⁵ and Y⁶ are bonds.In some embodiments, Y⁴, Y⁵ and Y⁶ are independently —CR^(a)R^(b)— or L.In some embodiments, Y⁴, Y⁵ and Y⁶ are independently L. In someembodiments, any one of Y⁴, Y⁵ and Y⁶ is a bond, and the remaining ofY⁴, Y⁵ and Y⁶ are independently —CR^(a)R^(b)— or L. In some embodiments,any one of Y⁴, Y⁵ and Y⁶ is a bond, and the remaining of Y⁴, Y⁵ and Y⁶are independently L. In some embodiments, any two of Y⁴, Y⁵ and Y⁶ arebonds, and the remaining of Y⁴, Y⁵ and Y⁶ is —CR^(a)R^(b)— or L. In someembodiments, any two of Y⁴, Y⁵ and Y⁶ are bonds, and the remaining ofY⁴, Y⁵ and Y⁶ is L.

In some embodiments, of any of the above embodiments of compounds ofFormula Iz, each R²⁷ is independently optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R²⁷ is halogen, provided that Y⁴,Y⁵ or Y⁶ is a bond.

The compounds of Formulae Ia-Iz, and all sub-embodiments detailedherein, may be used to treat a subject suffering from or at risk for anyof the protein kinase mediated diseases or conditions contemplatedherein.

In some embodiments, compounds of Formula I have the structure accordingto the following sub-generic structure Formula II:

all salts, prodrugs, tautomers and isomers thereof,

-   -   wherein:    -   A, R⁴, R⁵ and R⁶ are as defined with reference to Formula I; and    -   R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from the        group consisting of hydrogen, halogen, optionally substituted        lower alkyl, optionally substituted lower alkenyl, optionally        substituted lower alkynyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, —CN, —NO,        —CR^(a)R^(b)R²⁴, and -LR²⁴, where L and R²⁴ are as defined for        Formula I.

In some embodiments of compounds of Formula II, at least one of R¹²,R¹³, R¹⁴, R¹⁵ and R¹⁶ is other than hydrogen. In some embodiments, atleast two of R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are other than hydrogen. In someembodiments, at least three of R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are other thanhydrogen. In some embodiments, at least four of R¹², R¹³, R¹⁴, R¹⁵ andR¹⁶ are other than hydrogen. In some embodiments, R¹², R¹³, R¹⁴, R¹⁵ andR¹⁶ are other than hydrogen.

In some embodiments of compounds of Formula II, one of R¹², R¹³, R¹⁴,R¹⁵ and R¹⁶ is other than hydrogen, and the others of R¹², R¹³, R¹⁴, R¹⁵and R¹⁶ are each independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, R¹²is other than hydrogen and R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹³ is other than hydrogen, and R¹²,R¹⁴, R¹⁵ and R¹⁶ are each independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, R¹⁴ is other than hydrogen, and R¹², R¹³, R¹⁵ and R¹⁶ areeach independently hydrogen, halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio.

In some embodiments of compounds of Formula II, any two of R¹², R¹³,R¹⁴, R¹⁵ and R¹⁶ are independently other than hydrogen, and the othersof R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, R¹² and R¹³ are each independently other than hydrogen, andR¹⁴, R¹⁵ and R¹⁶ are each independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, R¹² and R¹⁴ are each independently other than hydrogen, andR¹³, R¹⁵ and R¹⁶ are each independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, R¹² and R¹⁵ are each independently other than hydrogen, andR¹³, R¹⁴ and R¹⁶ are each independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, R¹² and R¹⁶ are each independently other than hydrogen, andR¹³, R¹⁴ and R¹⁵ are each independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, R¹³ and R¹⁴ are each independently other than hydrogen, andR¹², R¹⁵ and R¹⁶ are each independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, R¹³ and R¹⁵ are each independently other than hydrogen, andR¹², R¹⁴ and R¹⁶ are each independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio.

In some embodiments of any of the above embodiments of compounds ofFormula II, wherein any of R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is designated asother than hydrogen, each such R¹², R¹³, R¹⁴, R¹⁵, or R¹⁶ isindependently -LR²⁴.

In some embodiments of any of the above embodiments of compounds ofFormula II, R⁵ is other than hydrogen, and R⁴ and R⁶ are hydrogen, or R⁴is other than hydrogen, and R⁵ and R⁶ are hydrogen, or R⁶ is other thanhydrogen, and R⁴ and R⁵ are hydrogen, or R⁴ and R⁵ are other thanhydrogen, and R⁶ is hydrogen, or R⁴ and R⁶ are other than hydrogen, andR⁵ is hydrogen, or R⁵ and R⁶ are other than hydrogen, and R⁴ ishydrogen, or R⁴, R⁵ and R⁶ are other than hydrogen.

In some embodiments of compounds of Formula II, the following compoundsare excluded:

-   -   R⁴, R⁵, R⁶, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen and A is        —CH₂—, —S— or —S(O)—;    -   R⁴, R⁶, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, R⁵ is —Br or        thiophen-3-yl, and A is —C(O)—;    -   R⁴ is 3,5 di-fluorophenyl, —NH₂, or —NO₂, R⁵, R⁶, R¹², R¹³, R¹⁴,        R¹⁵ and R¹⁶ are hydrogen, and A is —C(O)—;    -   R⁴ is NO₂, R⁵ is Br, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen,        and A is —C(O)—;    -   R⁵ is —Br, R⁴, R⁶, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and        A is —S(O)—;    -   R¹² is —CH₃ or —F, R⁶, R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A        is —C(O)—;    -   R¹² is —OH, R⁴, R⁶, R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, R⁵ is        thiophen-2-yl, and A is —C(O)—;    -   R¹² is —CF₃, R⁴, R⁵, R⁶, R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and        A is —S(O)₂—;    -   R¹³ is —OH or —OCH₃, R⁴, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen,        and A is —CH₂—;    -   R¹³ is —OCH₃, R⁵, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen, R⁴ is        —Br, and A is —CH₂—;    -   R¹³ is —OH or —OCH₃, R⁴, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen,        R⁵ is thiophen-2-yl, and A is —CHOH—;    -   R¹³ is

wherein

indicates the bond to the phenyl ring, R⁴, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ arehydrogen, R⁵ is thiophen-3-yl, and A is —CH₂—;

-   -   R¹³ is —F, —OH or —OCH₃, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen,        and A is —C(O)—;    -   R¹³ is —NO₂, —NH₂, or

wherein

indicates the bond to the phenyl ring, R⁴, R⁵, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶are hydrogen, and A is —C(O)—;

-   -   R¹³ is —F, —Cl, or —CF₃, R⁴, R⁵, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are        hydrogen, and A is —S(O)₂—;    -   R¹³ and R¹⁴ are —OH, R⁴, R⁶, R¹², R¹⁵ and R¹⁶ are hydrogen, R⁵        is thiophen-3-yl, and A is —CH₂—;    -   R¹⁴ is —OH or —OCH₃, R⁴, R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are        hydrogen, R⁵ is thiophen-2-yl, and A is —C(O)—;    -   R¹⁴ is —OCH₃, R⁴, R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen,        and A is —C(O)—;    -   R¹⁴ is —Cl, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, and A is        —C(O)—;    -   R¹ is

wherein

indicates the bond to the phenyl ring, R⁴, R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶are hydrogen, and A is —CH₂—;

-   -   R¹⁴ is —F, R⁴, R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, and A        is —S— or —S(O)₂—;    -   R¹⁴ is —CH₃, R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, R⁴ is        3-(hydroxymethyl)phenyl, and A is —S—;    -   R¹² and R¹⁶ are —F, R⁵, R⁶, R¹³, R¹⁴ and R¹⁵ are hydrogen, R⁴ is        3,5 difluorophenyl, and A is —C(O)—;    -   R¹² is —Cl, R¹³ is —Cl, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A        is —C(O)—;    -   R¹² is —F, R¹³ is —F, R⁵, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, R⁴        is 3,5 difluorophenyl, and A is —C(O)—;    -   R¹² is —F, R¹³ is —OH or —OCH₃, R⁴, R⁶, R¹⁴, R¹⁵ and R¹⁶ are        hydrogen, R⁵ is thiophen-2-yl, and A is —C(O)—;    -   R¹² is —F, R¹³ is —OCH₃, R⁴, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen,        R⁵ is —Br, and A is —C(O)—;    -   R¹² and R¹⁴ are —F, R⁵, R⁶, R¹³, R¹⁵ and R¹⁶ are hydrogen, R⁴ is        3,5 difluorophenyl, and A is —C(O)—;    -   R¹² is —CH₃, R¹⁵ is —F, R⁶, R¹³, R¹⁴ and R¹⁶ are hydrogen and A        is —C(O)—;    -   R¹² is —F, R¹⁵ is —Cl, R⁵, R⁶, R¹³, R¹⁴ and R¹⁶ are hydrogen, R⁵        is thiophen-2-yl and A is —C(O)—;    -   R¹² and R¹⁵ are —F, R⁵, R⁶, R¹⁴ and R¹⁶ are hydrogen, and A is        —C(O)—;    -   R¹² is halogen, R¹⁵ is —OH or —OCH₃, R⁶, R¹³, R¹⁴ and R¹⁶ are        hydrogen and A is —C(O)—;    -   R¹³ is —F, R¹⁵ is —NHS(O)₂C₁₋₃, R⁴, R⁵, R⁶, R¹³, R¹⁴ and R¹⁶ are        hydrogen and A is —C(O)—;    -   R¹³ and R¹⁵ are —OCH₃, R⁴, R⁵, R⁶, R¹², R¹⁴ and R¹⁶ are        hydrogen, and A is —CH₂—;    -   R¹³ and R¹⁵ are —Cl, R⁴, R⁵, R⁶, R¹², R¹⁴ and R¹⁶ are hydrogen,        and A is —S(O)₂—;    -   R¹³ is —OH and R¹⁵ is —OH or —OCH₃, R⁴, R⁶, R¹², R¹⁴ and R¹⁶ are        hydrogen, R⁵ is thiophen-3-yl, and A is —CH₂—;    -   R⁴, R⁶, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, A is —S(O)₂—,        and R⁵ is

wherein

indicates the bond to the 5-position of the 7-azaindole ring;

-   -   R⁵, R⁶, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, A is —S(O)₂—,        and R⁴ is

wherein

indicates the bond to the 4-position of the 7-azaindole ring;

-   -   R⁴, R⁵, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are hydrogen. A is —S(O)₂—,        and R⁶ is

wherein

indicates the bond to the 6-position of the 7-azaindole ring;

-   -   R¹³ is —CN, R⁴, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen, A is        —S(O)₂—, and R⁵ is

wherein

indicates the bond to the 5-position of the 7-azaindole ring;

-   -   R¹² is —Cl, R¹⁴ is —F or hydrogen, R⁴, R⁶, R¹³, R¹⁵ and R¹⁶ are        hydrogen, A is —S(O)₂—, and R⁵ is

wherein

indicates the bond to the 5-position of the 7-azaindole ring;

-   -   R¹⁴ is —NH₂, R⁴, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, A is        —S(O)₂—, and R⁵ is

wherein

indicates the bond to the 5-position of the 7-azaindole ring;

-   -   R⁶, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, A is —S(O)₂—, R⁴ is        —Cl, and R⁵ is

wherein

indicates the bond to the 5-position of the 7-azaindole ring;

-   -   R¹³ is —F, R⁴, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen, A is        —CH₂—, and R⁵ is 3-hydroxy-phenyl;    -   R¹⁴ is —N(CH₃)₂, R⁴, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, A        is —C(O)—, and R⁵ is 3-hydroxy-phenyl;    -   R¹⁴ is hydrogen or —Br, R⁴, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are        hydrogen, A is —S—, and R⁵ is 3-hydroxy-phenyl; and    -   R⁴, R⁶, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, A is —C(O)—,        and R⁵ is 3-hydroxy-phenyl.

In some embodiments of compounds of Formula II, at least one of R¹²,R¹³, R¹⁴, R¹⁵ and R¹⁶ is -LR²³, wherein R²⁴ is substituted methyl,optionally substituted C₂₋₆ alkyl, optionally substituted lower alkenyl,provided, however, that when R²⁴ is optionally substituted loweralkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O)₂, C(O)or C(S) of L, optionally substituted lower alkynyl, provided, however,that when R²⁴ is optionally substituted lower alkynyl, no alkyne carbonthereof is bound to N, S, O, S(O), S(O)₂, C(O) or C(S) of L, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl,provided, however, that R¹³ is not

and that R¹⁴ is not

wherein

indicates the bond to the phenyl ring; in further embodiments, R²⁴ isoptionally substituted C₂₋₆ alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, or substituted methyl, wherein methylis substituted with optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; in further embodiments, R⁵ is other thanhydrogen; in further embodiments, R⁴ and R⁶ are hydrogen.

In some embodiments of compounds of Formula II, R¹² is other thanhydrogen. In some embodiments, R¹² is -LR²⁴. In some embodiments, R¹² isother than hydrogen and R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹² is -LR²⁴ and R¹³, R¹⁴, R¹⁵ and R¹⁶are independently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio. In some embodiments, R¹² is -LR²⁴, anythree of R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio and theremaining of R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen. In some embodiments, R¹²is -LR²⁴, any two of R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen. Insome embodiments, R¹² is -LR²⁴, any one of R¹³, R¹⁴, R¹⁵ and R¹⁶ ishydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen. Insome embodiments, R¹² is -LR²⁴, and R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen.In some embodiments, R¹² is other than hydrogen, and R¹³, R¹⁴, R¹⁵ andR¹⁶ are hydrogen.

In other embodiments of compounds of Formula II, wherein R¹² is otherthan hydrogen, when R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen and A is —C(O)—,then R¹² is not —CH₃, —F, or —OH; and when R⁴, R⁵, R⁶, R¹³, R¹⁴, R¹⁵,and R¹⁶ are hydrogen, and A is —S(O)₂—, then R¹² is not —CF₃; and whenR¹² and R¹⁶ are —F, R⁵, R⁶, R¹³, R¹⁴ and R¹⁵ are hydrogen, and A is—C(O)—, R⁴ is not 3,5 difluorophenyl; and when R¹² is halogen, R⁶, R¹⁴.R¹⁵ and R¹⁶ are hydrogen, and A is —C(O)—, R¹³ is not halogen, —OH, or—OCH₃; and when R¹² and R¹⁴ are —F, R⁵, R⁶, R¹³, R¹⁵ and R¹⁶ arehydrogen, and A is —C(O)—, R⁴ is not 3,5 difluorophenyl; and when R¹⁵ ishalogen, —OH or —OCH₃, R⁶, R¹³, R¹⁴ and R¹⁶ are hydrogen, and A is—C(O)—, R¹¹ is not halogen; and when R¹⁵ is —F, R⁶, R¹³, R¹⁴ and R¹⁶ arehydrogen and A is —C(O)—, R¹² is not —CH₃; and when R¹² is —F, R⁴, R⁵,R⁶, R¹³, R¹⁴ and R¹⁶ are hydrogen and A is —C(O)—, R¹⁵ is not—NHS(O)₂CH₃; and when R¹² is —Cl, R¹⁴ is —F or hydrogen, R⁴, R⁶, R¹³,R¹⁵ and R¹⁶ are hydrogen, and A is —S(O)₂—, R⁵ is not

wherein

indicates the bond to the 5-position of the 7-azaindole ring.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹² is other than hydrogen, R⁵ is other than hydrogenand R⁴ and R⁶ are hydrogen; or R⁴ is other than hydrogen and R⁵ and R⁶are hydrogen; or R⁶ is other than hydrogen and R⁴ and R⁵ are hydrogen;or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen; or R⁴ and R⁶are other than hydrogen and R⁵ is hydrogen; or R⁵ and R⁶ are other thanhydrogen and R⁴ is hydrogen; or R⁴, R⁵ and R⁶ are all other thanhydrogen.

In some embodiments of compounds of Formula II, R¹³ is other thanhydrogen. In some embodiments, R¹³ is -LR²⁴. In some embodiments, R¹³ isother than hydrogen and R¹², R¹⁴, R¹⁵ and R¹⁶ are each independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹³ is -LR²⁴ and R¹², R¹⁴, R¹⁵ and R¹⁶are each independently hydrogen, halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio. In some embodiments, R¹³ is -LR²⁴,any three of R¹², R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio and theremaining of R¹², R¹⁴, R¹⁵ and R¹⁶ is hydrogen. In some embodiments, R¹³is -LR²⁴, any two of R¹², R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen. Insome embodiments, R¹³ is -LR²⁴, any one of R¹³, R¹⁴, R¹⁵ and R¹⁶ isindependently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio, and the remaining of R¹², R¹⁴, R¹⁵ and R¹⁶are hydrogen. In some embodiments, R¹³ is -LR⁷⁴, and R¹², R¹⁴, R¹⁵ andR¹⁶ are hydrogen. In some embodiments, R¹³ is other than hydrogen, andR¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen.

In other embodiments of compounds of Formula II, wherein R¹³ id otherthan hydrogen, when R⁴, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A is —CH—or —CH(OH)—, then R¹³ is not —OH or —OCH₃; and when R⁵, R⁶, R¹², R¹⁴,R¹⁵ and R¹⁶ are hydrogen, and A is —CH₂—, then R¹³ is not —OCH₃; andwhen R¹³ is

wherein

indicates the bond to the phenyl ring, R⁴, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ arehydrogen, and A is —CH₂—, then R⁵ is not thiophen-3-yl; and when R⁶,R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A is —C(O)—, then R¹³ is not —F,—OH, or —OCH₃; and when R⁴, R⁵, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen,and A is —C(O)—, then R¹³ is not —NO₂, —NH₂, or

wherein

indicates the bond to the phenyl ring; and when R⁴, R⁵, R⁶, R¹², R¹⁴,R¹⁵ and R¹⁶ are hydrogen, and A is —S(O)₂—, then R¹³ is not —F, —Cl, or—CF₃; and when R¹³ and R¹⁴ are —OH, R⁴, R⁶, R¹², R¹⁵ and R¹⁶ arehydrogen and A is —CH₂, R⁵ is not thiophen-3-yl; and when R⁶, R¹⁴, R¹⁵and R¹⁶ are hydrogen and A is —C(O)—, then R¹¹ and R¹² are not both Cl;and when R¹² and R¹³ are both —F, R⁵, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogenand A is —C(O)—, then R⁴ is not 3,5-difluorophenyl; and when R¹³ is —OHor —OCH₃, R¹² is —F, R⁴, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A is—C(O)—, then R⁵ is not thiophen-2-yl; and when R¹³ is —OCH₃, R¹² is —F,R⁴, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A is —C(O)—, then R⁵ is not—Br; and when R⁶, R¹², R¹⁴ and R¹⁵ are hydrogen, R¹⁶ is —CH₃ and A is—C(O)—, then R¹³ is not —F; and when R¹³ is —Cl, R¹⁶ is —F, R⁴, R⁶, R¹²,R¹⁴ and R¹⁵ are hydrogen, and A is —C(O)—, then R⁵ is not thiophen-2-yl;and when R⁶, R¹², R¹⁴ and R¹⁵ are hydrogen and A is —C(O)—, then R¹³ andR¹⁶ are not both —F; and when R⁶, R¹², R¹⁴ and R¹⁵ are hydrogen, R¹⁶ ishalogen, and A is —C(O)—, then R¹³ is not —OH or —OCH₃; and when R⁴, R⁵,R⁶, R¹², R¹⁴ and R¹⁵ are hydrogen, R¹³ is —NHS(O)₂CH₃, and A is —C(O)—,then R¹⁶ is not F; and when R⁴, R⁵, R⁶, R¹², R¹⁴ and R¹⁶ are hydrogen,and A is —CH₂—, then R¹³ and R¹⁵ are not both —OCH₃; and when R⁴, R⁵,R⁶, R¹², R¹⁴ and R¹⁶ are hydrogen, and A is —S(O)₂—, then R¹³ and R¹⁵are not both —Cl; and when R¹³ is —OH, R¹⁵ is —OH or —OCH₃, R⁴, R⁶, R¹²,R¹⁴ and R¹⁶ are hydrogen, and A is —CH₂—, then R⁵ is not thiophen-3-yl;and when R¹³ is —F, R⁴, R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A is—CH₂—, then R⁵ is not 3-hydroxy-phenyl and when R¹³ is —CN, R⁴, R⁶, R¹²,R¹⁴, R¹⁵ and R¹⁶ are hydrogen, A is —S(O)₂—, then R⁵ is not

wherein

indicates the bond to the 5-position of the 7-azaindole ring.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹³ is other than hydrogen, R⁵ is other than hydrogenand R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵ and R⁶are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ are hydrogen,or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen, or R⁴ and R⁶are other than hydrogen and R⁵ is hydrogen, or R⁵ and R⁶ are other thanhydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other than hydrogen.

In some embodiments of compounds of Formula II, R¹⁴ is other thanhydrogen. In some embodiments, R¹⁴ is -LR²⁴. In some embodiments, R¹⁴ isother than hydrogen and R¹², R¹³, R¹⁵ and R¹⁶ are each independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹⁴ is -LR²⁴, and R¹², R¹³, R¹⁵ and R¹⁶are independently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio. In some embodiments, R¹⁴ is -LR²⁴, anythree of R¹², R¹³, R¹⁵ and R¹⁶ are independently hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio, and theremaining of R¹², R¹³, R¹⁵ and R¹⁶ is hydrogen. In some embodiments, R¹⁴is -LR²⁴, any two of R¹², R¹³, R¹⁵ and R¹⁶ are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio, and the remaining of R¹², R¹³, R¹⁵ and R¹¹ are hydrogen. Insome embodiments, R¹⁴ is -LR²⁴, any one of R¹², R¹³, R¹⁵ and R¹⁶ areindependently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio, and the remaining of R¹², R¹³, R¹⁵ and R¹⁶are hydrogen. In some embodiments, R¹⁴ is -LR²⁴, and R¹², R¹³, R¹⁵ andR¹⁶ are hydrogen. In some embodiments, R¹⁴ is other than hydrogen, andR¹², R¹³, R¹⁵ and R¹⁶ are hydrogen.

In other embodiments of compounds of Formula II, wherein R¹⁴ is otherthan hydrogen, when R⁴, R⁶, R¹², R¹³, R¹⁵, and R¹⁶ are hydrogen, R⁵ isthiophen-2-yl and A is —C(O)—, then R¹⁴ is not —OH, or —OCH₃; and whenR⁴, R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen and A is —C(O)—, then R¹⁴is not —OCH₃; and when R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen and A is—C(O)—, then R¹⁴ is not —Cl; and when R⁴, R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶are hydrogen and A is —CH₂—, then R¹⁴ is not

wherein

indicates the bond to the phenyl ring; and when R⁴, R⁵, R⁶, R¹², R¹³,R¹⁵ and R¹⁶ are hydrogen and A is —S— or —S(O)₂—, then R¹⁴ is not —F;and when R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, R⁴ is3-(hydroxymethyl)phenyl and A is —S—, then R¹⁴ is not —CH₃; and when R⁵,R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, R¹⁴ is 3,5-difluorophenyl and Ais —C(O)—, R¹²¹ and R¹⁴ are not both —F; and when R¹⁴ is —N(CH₃)₂, R⁴,R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, and A is —CH₂—, then R⁵ is not3-hydroxy-phenyl; and when R¹⁴ is —Br, R⁴, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ arehydrogen, and A is —S—, then R⁵ is not 3-hydroxy-phenyl; and when R¹² is—Cl, R¹⁴ is —F, R⁴, R⁶, R¹³, R¹⁵ and R¹⁶ are hydrogen, and A is —S(O)₂—,then R⁵ is not

wherein

indicates the bond to the 5-position of the 7-azaindole ring; and whenR¹⁴ is —NH₂, R⁴, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, and A is—S(O)—, then R⁵ is not

wherein

indicate the bond to the 5-position of the 7-azaindole ring; and whenR⁴, R⁶, R¹², R¹⁵ and R¹⁶ are hydrogen, R¹³ and R¹⁴ are —OH, and A is—CH₂—, then R⁵ is not thiophen-3-yl.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹⁴ is other than hydrogen, R⁵ is other than hydrogenand R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵ and R⁶are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ are hydrogen,or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen, or R⁴ and R⁶are other than hydrogen and R⁵ is hydrogen, or R⁵ and R⁶ are other thanhydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other than hydrogen.

In some embodiments of compounds of Formula II, R¹² and R¹⁶ are otherthan hydrogen. In some embodiments, R¹² and R¹⁶ are independently -LR²⁴.In some embodiments, R¹² and R¹⁶ are other than hydrogen and R¹³, R¹⁴and R¹⁵ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, R¹²and R¹⁶ are independently -LR²⁴ and R¹³, R¹⁴ and R¹⁵ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹² and R¹⁶ are independently -LR²⁴, anytwo of R¹³, R¹⁴ and R¹⁵ are independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio, and theremaining of R¹³, R¹⁴ and R¹⁵ is hydrogen. In some embodiments, R¹² andR¹⁶ are independently -LR²⁴, any one of R¹³, R¹⁴ and R¹⁵ isindependently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio, and the remaining of R¹³, R¹⁴ and R¹⁵ arehydrogen. In some embodiments, R¹² and R¹⁶ are independently -LR²⁴, andR¹³, R¹⁴ and R¹⁵ are hydrogen. In some embodiments, R¹² and R¹⁶ areother than hydrogen, and R¹³, R¹⁴ and R¹⁵ are hydrogen. In otherembodiments, wherein R¹² and R¹⁶ are other than hydrogen, when R⁵, R⁶,R¹³, R¹⁴ and R¹⁵ are hydrogen and A is —C(O)—, then R¹² and R¹⁶ are notboth —F.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹² and R¹⁶ is other than hydrogen, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵and R⁶ are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen, or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen, or R⁴and R⁶ are other than hydrogen and R⁵ is hydrogen, or R⁵ and R⁶ areother than hydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other thanhydrogen.

In some embodiments of compounds of Formula II, R¹² and R¹³ are otherthan hydrogen. In some embodiments, R¹² and R¹³ are independently -LR²⁴.In some embodiments, R¹² and R¹³ are other than hydrogen and R¹⁴, R¹⁵and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, R¹²and R¹³ are independently -LR²⁴, and R¹⁴, R¹⁵ and R¹⁶ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹² and R¹³ are independently -LR²⁴, anytwo of R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio, and theremaining of R¹⁴, R¹⁵ and R¹⁶ is hydrogen. In some embodiments, R¹² andR¹³ are independently -LR²⁴, any one of R¹⁴, R¹⁵ and R¹⁶ isindependently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio, and the remaining of R¹⁴, R¹⁵ and R¹⁶ arehydrogen. In some embodiments, R¹² and R¹³ are independently -LR²⁴, andR¹⁴, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, R¹² and R¹³ areother than hydrogen and R¹⁴, R¹⁵ and R¹⁶ are hydrogen. In otherembodiments, wherein R¹² and R¹³ are other than hydrogen, when R⁶, R¹⁴,R¹⁵ and R¹⁶ are hydrogen, A is —C(O)—, and R¹³ is halogen, —OH, or—OCH₃, then R¹² is not halogen. In alternate embodiments, when R¹² andR¹³ are other than hydrogen, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen and A is—C(O)—, then both R¹² and R¹³ are not halogen; and when R¹² and R¹³ areother than hydrogen, R⁴, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogen, and A is—C(O)—, R¹² is —F and R¹³ is —OH or —OCH₃, then R⁵ is not —Br orthiophen-2-yl.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹² and R¹³ is other than hydrogen, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵and R⁶ are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen, or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen, or R⁴and R⁶ are other than hydrogen and R⁵ is hydrogen, or R⁵ and R⁶ areother than hydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other thanhydrogen.

In some embodiments of compounds of Formula II, R¹² and R¹⁴ are otherthan hydrogen. In some embodiments, R¹² and R¹⁴ are independently -LR²⁴.In some embodiments, R¹² and R¹⁴ are other than hydrogen and R¹³, R¹⁵and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, R¹²and R¹⁴ are independently -LR²⁴, and R¹³, R¹⁵ and R¹⁶ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹² and R¹⁴ are independently -LR²⁴, andany one of R¹³, R¹⁵ and R¹⁶ is independently hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio, and theremaining of R¹³, R¹⁴ and R¹⁶ is hydrogen. In some embodiments, R¹² andR¹⁴ are independently -LR²⁴, and any two of R¹³, R¹⁵ and R¹⁶ areindependently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio and the remaining of R¹³, R¹⁵ and R¹⁶ ishydrogen. In some embodiments, R¹² and R¹⁴ are independently -LR²⁴ andR¹³, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, R¹² and R¹⁴ areother than hydrogen and R¹³, R¹⁵ and R¹⁶ are hydrogen. In someembodiments, wherein R¹² and R¹⁴ are other than hydrogen, when R⁵, R⁶,R¹³, R¹⁵ and R¹⁶ are hydrogen, A is —C(O)—, and R⁴ is 3,5difluorophenyl, then R¹² and R¹⁴ are not both —F; and when R¹² is —Cl,R¹⁴ is —F, R⁴, R⁶, R¹³, R¹⁵ and R¹⁶ are hydrogen, and A is —S(O)₂—, thenR⁵ is not

wherein

indicates the bond to the 5-position of the 7-azaindole ring.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹² and R¹⁴ is other than hydrogen, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵and R⁶ are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen, or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen, or R⁴and R⁶ are other than hydrogen and R⁵ is hydrogen, or R³ and R⁶ areother than hydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other thanhydrogen.

In some embodiments of compounds of Formula II, R¹² and R¹⁵ are otherthan hydrogen. In some embodiments, R¹² and R¹⁵ are independently -LR²⁴.In some embodiments, R¹² and R¹⁵ are other than hydrogen and R¹³, R¹⁴and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, R¹²and R¹⁵ are independently -LR²⁴ and R¹³, R¹⁴ and R¹⁶ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹² and R¹⁵ are independently -LR²⁴, anytwo of R¹³, R¹⁴ and R¹⁶ are independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio and theremaining of R¹³, R¹⁴ and R¹⁶ is hydrogen. In some embodiments, R¹² andR¹⁵ are independently -LR²⁴, any one of R¹³, R¹⁴ and R¹⁶ is hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹³, R¹⁴ and R¹⁶ are hydrogen. In someembodiments, R¹² and R¹⁵ are independently -LR²⁴ and R¹³, R¹⁴ and R¹⁶are hydrogen. In some embodiments, R¹² and R¹⁵ are other than hydrogenand R¹³, R¹⁴ and R¹⁶ are hydrogen. In other embodiments, wherein R¹² andR¹⁵ are other than hydrogen, when R⁶, R¹³, R¹⁴ and R¹⁶ are hydrogen andA is —C(O)—, then R¹² and R¹⁵ are not both halogen; and when R⁶, R¹³,R¹⁴ and R¹⁶ are hydrogen, A is —C(O)—, and R¹² is —CH₃, then R¹⁵ is not—F; and when R⁶, R¹³, R¹⁴ and R¹⁶ are hydrogen, A is —C(O)—, and R¹² ishalogen, then R¹⁵ is not —OH or —OCH₃; and when R⁴, R⁶, R¹³, R¹⁴ and R¹⁶are hydrogen, A is —C(O)—, and R¹² is —F then R¹⁵ is not NHS(O)₂CH₃.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹² and R¹⁵ is other than hydrogen, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵and R⁶ are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen, or R⁴ and R⁵ are other than hydrogen and R¹ is hydrogen, or R⁴and R⁶ are other than hydrogen and R⁵ is hydrogen, or R⁵ and R⁶ areother than hydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other thanhydrogen.

In some embodiments of compounds of Formula II, R¹³ and R¹⁴ are otherthan hydrogen. In some embodiments, R¹³ and R¹⁴ are independently -LR²⁴.In some embodiments, R¹³ and R¹⁴ are other than hydrogen and R¹², R¹⁵and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, R¹³and R¹⁴ are independently -LR²⁴ and R¹², R¹⁵ and R¹⁶ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹³ and R¹⁴ are independently -LR²⁴, anytwo of R¹², R¹⁵ and R¹⁶ are independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio and theremaining of R¹², R¹⁵ and R¹⁶ is hydrogen. In some embodiments, R¹³ andR¹⁴ are independently -LR²⁴, any one of R¹², R¹⁵ and R¹⁶ is hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹¹ and R¹⁶ are hydrogen. In someembodiments, R¹³ and R¹⁴ are independently -LR²⁴ and R¹², R¹⁵ and R¹⁶are hydrogen. In some embodiments, R¹³ and R¹⁴ are other than hydrogenand R¹², R¹⁵ and R¹⁶ are hydrogen. In other embodiments, wherein R¹³ andR¹⁴ are other than hydrogen, when R⁴, R⁶, R¹², R¹⁵ and R¹⁶ are hydrogen,A is —CH₂—, and R⁵ is thiophen-3-yl, then R¹³ and R¹⁴ are not both —OH.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹³ and R¹⁴ is other than hydrogen, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵and R⁶ are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen, or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen, or R⁴and R⁶ are other than hydrogen and R⁵ is hydrogen, or R⁵ and R⁶ areother than hydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other thanhydrogen.

In some embodiments of compounds of Formula II, R¹³ and R¹⁵ are otherthan hydrogen. In some embodiments, R¹³ and R¹⁵ are independently -LR²⁴.In some embodiments, R¹³ and R¹⁵ are other than hydrogen and R¹², R¹⁴and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, R¹³and R¹⁵ are independently -LR²⁴ and R¹², R¹⁴ and R¹⁶ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, R¹³ and R¹⁵ are independently -LR²⁴, twoof R¹², R¹⁴ and R¹⁶ are independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio and theremaining of R¹¹, R¹⁴ and R¹⁶ is hydrogen. In some embodiments, R¹³ andR¹⁵ are independently -LR²⁴, one of R¹², R¹⁴ and R¹⁶ is hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹⁴ and R¹⁶ are hydrogen. In someembodiments, R¹³ and R¹⁵ are independently -LR²⁴ and R¹², R¹⁴ and R¹⁶are hydrogen. some embodiments, R¹³ and R¹⁵ are other than hydrogen andR¹², R¹⁴ and R¹⁶ are hydrogen. In other embodiments, wherein R¹³ and R¹⁵are other than hydrogen, when R⁴, R⁵, R⁸, R¹², R¹⁴ and R¹⁶ are hydrogenand A is —CH₂—, then R¹³ and R¹⁵ are not both —OCH₃; and when R⁴, R⁵,R⁶, R¹², R¹⁴ and R¹¹ are hydrogen and A is —S(O)₂—, then R¹³ and R¹⁵ arenot both —Cl; and when R⁴, R⁶, R¹², R¹⁴ and R¹⁶ are hydrogen, A is—CH₂—, R¹³ is —OH and R¹⁵ is —OH or —OCH, then R⁵ is not thiophen-3-yl.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹³ and R¹⁵ is other than hydrogen, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen, or R⁴ is other than hydrogen and R⁵and R⁶ are hydrogen, or R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen, or R⁴ and R⁵ are other than hydrogen and R⁶ is hydrogen, or R⁴and R⁶ are other than hydrogen and R⁵ is hydrogen, or R⁵ and R⁶ areother than hydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶ are other thanhydrogen.

In some embodiments of compounds of Formula II, R¹³ is -LR²⁴, provided,however, that when A is —CH₂—, —CH(OH)— or —C(O)—, and R¹², R¹⁴, R¹⁵,and R¹⁵ are hydrogen, then R¹³ is not —OH, —OCH₃, or

wherein

indicates the bond to the phenyl ring; and when R⁴, R⁵, R⁶, R¹², R¹⁴,R¹⁵, and hydrogen and A is —C(O)—, R¹³ is not NH₂, or

wherein

indicates the bond to the phenyl ring; and when R⁴, R⁵, R⁶, R¹², R¹⁴ andR¹⁶ are hydrogen and A is —CH₂—, R¹³ and R¹⁵ are not both —OCH₃; andwhen R⁴, R⁶, R¹², R¹⁴ and R¹⁶ are hydrogen, A is —CH₂—, R¹⁵ isthiophen-3-yl, R¹³ is —OH, R¹¹ is not —OH or —OCH₃; and when R⁴, R⁶,R¹², R¹⁵ and R¹⁶ are hydrogen, A is —CH₂—, and R⁵ is thiophen-3-yl, R¹³and R¹⁴ are not both —OH; and when R⁴, R⁶, R¹⁴, R¹⁵ and R¹⁶ are hydrogenand A is —C(O)—, R¹² is —F, R⁵ is —Br or thiophen-2-yl, R¹³ is not —OHor —OCH₃; and when R¹², R¹⁴, and R¹⁵ are hydrogen, A is —C(O)—, and R¹⁶is halogen, R¹¹ is not —OH or —OCH₃; and when R⁴, R⁵, R⁶, R¹², R¹⁴, andR¹⁵ are hydrogen, A is —C(O)—, and R¹⁶ is —F, R¹¹ is not —NHS(O)₂CH₃. Infurther embodiments, R¹³ is -LR²⁴ and L is —NHS(O)₂CH₂—, —O—, or—O—CH₂—, R²⁴ is not H, or when L is —NHS(O)₂— or —O—, R²⁴ is not CH₃. Infurther embodiments, where R¹³ is -LR²⁴, one of R¹², R¹⁴, R¹⁵, and R¹⁶is other than hydrogen and the remaining of R¹², R¹⁴, R¹⁵, and R¹⁶ arehydrogen. In further embodiments, where R¹³ is -LR²⁴, two of R¹², R¹⁴,R¹⁵, and R¹⁶ are independently other than hydrogen and the remaining twoof R¹², R¹⁴, R¹⁵, and R¹⁶ are hydrogen. In some embodiments where R¹³ is-LR²⁴, R¹⁴ and R¹⁵ are hydrogen, and at least one of R¹² and R¹⁶ isother than hydrogen. In further embodiments, where R¹³ is -LR²⁴, R¹⁴ andR¹⁵ are hydrogen, and at least one of R¹² and R¹⁶ is other thanhydrogen, L is -(alk)_(a)-NR²⁵-(alk)_(b)-,-(alk)_(a)-C(O)NR²⁵-(alk)_(b)-, -(alk)_(a)-OC(O)NR²⁵-(alk)_(b)-,-(alk)_(a)-OC(S)NR²⁵-(alk)_(b)-, -(alk)_(a)-C(S)NR²⁵-(alk)_(b)-,-(alk)_(a)-S(O)₂NR²⁵-(alk)_(b)-, -(alk)_(a)-NR²⁵C(O)-(alk)_(b)-,-(alk)_(a)-NR²⁵C(S)-(alk)_(b)-, -(alk)_(a)-NR²⁵C(O)NR²⁵-(alk)_(b)-,-(alk)_(a)-NR²⁵C(S)NR²⁵-(alk)_(b)-, -(alk)_(a)-NR²⁵C(O)O-(alk)_(b)-,-(alk)_(a)-NR²⁵C(S)O-(alk)_(b)-, -(alk)_(a)-NR²⁵S(O)₂-(alk)_(b)-, or-(alk)_(a)-NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein a, b, R²⁵ and alk are asdefined for Formula I.

In further embodiments of compounds of Formula II, where R¹³ is -LR²⁴,R¹⁴ and R¹⁵ are hydrogen, and at least one of R¹² and R¹⁶ is other thanhydrogen, L is —NR²⁵—, —NR²⁵-(alk)_(b)-, —C(O)NR²⁵-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —C(S)NR²⁵-(alk)_(b)-,—S(O)₂NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-,—NR²⁵C(O)NR²⁵-(alk)_(b)-, —NR²⁵C(S)NR²⁵-(alk)_(b)-,—NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-, —NR²⁵S(O)₂-(alk)_(b)-, or—NR²⁵S(O)₂NR²⁵-(alk)_(b)-.

In further embodiments of compounds of Formula II, where R¹³ is -LR²⁴,R¹⁴ and R¹⁵ are hydrogen, and at least one of R¹² and R¹⁶ is other thanhydrogen, L is —NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-. In furtherembodiments where R¹³ is -LR²⁴, R¹⁴ and R¹⁵ are hydrogen, and at leastone of R¹² and R¹⁶ is other than hydrogen, L is —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵S(O)₂-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-. In furtherembodiments where R¹³ is -LR²⁴, R¹⁴ and R¹⁵ are hydrogen, and at leastone of R¹² and R¹⁶ is other than hydrogen, L is —NR²⁵C(O)O-(alk)_(b)-,—NR²⁵C(S)O-(alk)_(b)-, —OC(O)NR²⁵-(alk)_(b)-, or —OC(S)NR²⁵-(alk)_(b)-.In some embodiments of any of the above embodiments where R¹³ is -LR²⁴,R⁵ is other than hydrogen and R⁴ and R⁶ are hydrogen, or R⁴ is otherthan hydrogen and R⁵ and R⁶ are hydrogen, or R⁶ is other than hydrogenand R⁴ and R⁵ are hydrogen, or R⁴ and R⁵ are other than hydrogen and R⁶is hydrogen, or R⁴ and R⁶ are other than hydrogen and R⁵ is hydrogen, orR⁵ and R⁶ are other than hydrogen and R⁴ is hydrogen, or R⁴, R⁵ and R⁶are other than hydrogen.

In some embodiments of compounds of Formula II, A is —CR^(a)R^(b)— or—C(O)—, R¹³ is -LR²⁴, R¹⁴ and R¹⁵ are hydrogen, R¹² and R¹⁶ areindependently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio, wherein one of R¹² and R¹⁶ is other thanhydrogen, and wherein L is —NR²⁵-(alk)_(b)-, —C(O)NR²⁵-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, —OC(S)NR²⁵-(alk)_(b)-, —C(S)NR²⁵-(alk)_(b)-,—S(O)_(b)NR²⁵-(alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-,—NR²⁵C(O)NR²⁵-(alk)_(b)-, —NR²⁵C(S)NR²⁵-(alk)_(b)-,—NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-, —NR²⁵S(O)₂-(alk)_(b)-, or—NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein b and R²⁵ are as defined for FormulaI, alk is C₁₋₃ alkylene optionally substituted with fluoro or optionallyfluoro substituted lower alkyl, and R²⁴ is hydrogen, provided, however,that said hydrogen would not be attached to S(O)₂—, optionally fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroarylare optionally substituted with halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio, and R^(a) and R^(b) areindependently hydrogen, halogen, optionally fluoro substituted loweralkyl or optionally fluoro substituted lower alkoxy, provided, however,that when R⁴, R⁵, R⁶, R¹², R¹⁴, and R¹⁵ are hydrogen, A is —C(O)—, andR¹⁶ is —F, then R¹³ is not —NHS(O)₂CH₃. In other embodiments, R¹² andR¹⁶ are independently halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio. In other embodiments, A is —CH₂—. In otherembodiments, A is —C(O)—. In other embodiments, R⁴ is other thanhydrogen and R⁵ and R⁶ are hydrogen. In other embodiments, A is —CH₂—,R⁴ is other than hydrogen and R⁵ and R⁶ are hydrogen. In otherembodiments, A is —C(O)—, R⁴ is other than hydrogen and R⁵ and R⁶ arehydrogen. In other embodiments, R⁵ is other than hydrogen and R⁴ and R⁶are hydrogen. In other embodiments, A is —CH₂—, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen. In other embodiments, A is —C(O)—,R⁵ is other than hydrogen and R⁴ and R⁶ are hydrogen. In otherembodiments, R⁶ is other than hydrogen and R⁴ and R⁵ are hydrogen. Inother embodiments, A is —CH₂—, R⁶ is other than hydrogen and R⁴ and R⁵are hydrogen. In other embodiments, A is —C(O)—, R⁶ is other thanhydrogen and R⁴ and R⁵ are hydrogen. In other embodiments, R⁴ and R⁵ areother than hydrogen and R⁶ is hydrogen. In other embodiments, R⁴ and R⁶are other than hydrogen, and R⁵ is hydrogen. In other embodiments, R⁴and R⁵ are hydrogen, and R⁶ is other than hydrogen. In otherembodiments, R⁴, R⁵, and R⁶ are other than hydrogen.

In some embodiments of compounds of Formula II, A is —CR^(a)R^(b)— or—C(O)—, R¹³ is -LR²⁴, R¹⁴ and R¹⁵ are hydrogen, R¹² and R¹⁶ areindependently hydrogen, halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio, wherein one of R¹² and R¹⁶ is other thanhydrogen, and wherein L is —NR²⁵— (alk)_(b)-, —NR²⁵C(O)-(alk)_(b)-,—NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein b and R²⁵are as defined for Formula I, alk is C₁₋₃ alkylene optionallysubstituted with fluoro or optionally fluoro substituted lower alkyl,R²⁴ is hydrogen provided, however, that said hydrogen would not beattached to S(O)₂—, optionally fluoro substituted lower alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withhalogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, and optionally fluoro substituted loweralkylthio, R^(a) and R^(b) are independently hydrogen, halogen,optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy, one of R⁴ and R⁵ is other than hydrogen and R⁶is hydrogen. In other embodiments, R¹⁶ is hydrogen. In otherembodiments, R¹² is hydrogen. In other embodiments, R¹² and R¹⁶ areindependently halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio. In other embodiments, A is —CH₂—. In otherembodiments, A is —C(O)—. In other embodiments, R⁴ is other thanhydrogen and R⁵ and R⁶ are hydrogen. In other embodiments, A is —CH₂—,R⁴ is other than hydrogen and R⁵ and R⁶ are hydrogen. In otherembodiments, A is —C(O)—, R⁴ is other than hydrogen and R⁵ and R⁶ arehydrogen. In other embodiments, R⁵ is other than hydrogen and R⁴ and R⁶are hydrogen. In other embodiments, A is —CH₂—, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen. In other embodiments, —C(O)—, R⁵ isother than hydrogen and R⁴ and R⁶ are hydrogen. In other embodiments, R⁶is other than hydrogen and R⁴ and R⁵ are hydrogen. In other embodiments,A is —CH₂—, R⁶ is other than hydrogen and R⁴ and R⁵ are hydrogen. Inother embodiments, A is —C(O)—, R⁶ is other than hydrogen and R⁴ and R⁵are hydrogen. In other embodiments, R⁴ and R⁵ are other than hydrogenand R⁶ is hydrogen. In other embodiments, R⁴ and R⁶ are other thanhydrogen and R⁵ is hydrogen. In other embodiments, R⁴ and R⁵ arehydrogen and R⁶ is other than hydrogen. In other embodiments, R⁴, R⁵,and R⁶ are other than hydrogen.

In some embodiments of compounds of Formula II, A is —CR^(a)R^(b)— or—C(O)—, R¹³ is -LR²⁴, R¹² is halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio, one of R¹⁴, R¹⁵, and R¹⁶ arehalogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the other two are hydrogen, L is —NR²⁵— (alk)-,—NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein band R²⁵ are as defined for Formula I, alk is C₁₋₃ alkylene optionallysubstituted with fluoro or optionally fluoro substituted lower alkyl,R²⁴ is hydrogen provided, however, that said hydrogen would not beattached to S(O) or S(O)₂, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, R^(a) and R^(b) are independently hydrogen, halogen,optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy, one of R⁴ and R⁵ is other than hydrogen and R⁶is hydrogen. In other embodiments, R⁴ is hydrogen and R⁵ is other thanhydrogen. In other embodiments, R⁵ is hydrogen and R⁴ is other thanhydrogen. In other embodiments, A is —CH₂—, R⁵ is hydrogen and R⁴ isother than hydrogen. In other embodiments, A is —C(O)—, R⁵ is hydrogenand R⁴ is other than hydrogen. In other embodiments, A is —CH₂—, R⁴ ishydrogen and R⁵ is other than hydrogen. In other embodiments, A is—C(O)—, R⁴ is hydrogen and R⁵ is other than hydrogen.

In some embodiments of compounds of Formula II, A is —CR^(a)R^(b)— or—C(O)—, R¹³ is -LR²⁴, R¹², R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio, where at least one of R¹², R¹⁴, R¹⁵ and R¹⁶ is other thanhydrogen, L is —NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-,—NR²⁵S(O)₂-(alk)₆-, —NR²⁵C(O)NR²⁵-(alk)_(b)-, —NR²⁵C(S)NR²⁵-(alk)_(b)-,or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein b and R²⁵ are as defined forFormula I, alk is C₁₋₃ alkylene optionally substituted with fluoro oroptionally fluoro substituted lower alkyl, R²⁴ is hydrogen provided,however, that said hydrogen would not be attached to S(O)₂, optionallysubstituted lower alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl, R^(a) and R^(b) are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy, provided, however, that when R⁴, R⁵, R⁶, R¹²,R¹⁴, and R¹⁵ are hydrogen, A is —C(O)—, and R¹⁶ is —F, then R¹³ is not—NHS(O)₂C₁₋₃. In further embodiments, R¹² is other than hydrogen andR¹⁴, R¹⁵ and R¹⁶ are hydrogen. In further embodiments, R¹⁶ is other thanhydrogen and R¹², R¹⁴ and R¹⁶ are hydrogen. In further embodiments, atleast two of R¹², R¹⁴, R¹⁵ and R¹⁶ are other than hydrogen. In furtherembodiments, R¹² and R¹⁶ are other than hydrogen and R¹⁴ and R¹⁵ arehydrogen. In further embodiments, R⁵ is other than hydrogen and R⁴ andR⁶ are hydrogen. In further embodiments, R⁴ is other than hydrogen andR⁵ and R⁶ are hydrogen.

In some embodiments of compounds of Formula II, A is —CR^(a)R^(b)— or—C(O)—, R¹³ is -LR²⁴, R¹², R¹⁴, R¹⁵ and R¹⁶ are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio, where at least one of R¹², R¹⁴, R¹⁵ and R¹⁶ is other thanhydrogen, L is —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—OC(O)NR²⁵-(alk)_(b)-, or —OC(S)NR²⁵-(alk)_(b)-, wherein b and R²⁵ areas defined for Formula I, alk is C₁₋₃ alkylene optionally substitutedwith fluoro or optionally fluoro substituted lower alkyl, R²⁴ ishydrogen, optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, R^(a) and R^(b)are independently hydrogen, halogen, optionally fluoro substituted loweralkyl, and optionally fluoro substituted lower alkoxy. In furtherembodiments, R¹² is other than hydrogen and R¹⁴, R¹⁵ and R¹⁶ arehydrogen. In further embodiments, R¹⁶ is other than hydrogen and R¹²,R¹⁵ and R¹⁶ are hydrogen. In further embodiments, at least two of R¹²,R¹⁴, R¹⁵ and R¹⁶ are other than hydrogen. In further embodiments, R¹²and R¹⁶ are other than hydrogen and R¹⁴ and R¹⁵ are hydrogen. In furtherembodiments, R⁵ is other than hydrogen and R⁴ and R⁶ are hydrogen. Infurther embodiments, R⁴ is other than hydrogen and R⁵ and R⁶ arehydrogen.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹³ is -LR²⁴, -LR²⁴ is not —NH₂, —OH, —OCH₃,—NHS(O)₂CH₃

wherein

indicates the bond to the phenyl ring.

In some embodiments of compounds of Formula II, R¹⁴ is -LR¹⁴, provided,however, that when R⁴, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen, R⁵ ishydrogen or thiophen-2-yl and A is —C(O)—, then R¹⁴ is not —OH, or—OCH₃; and when R⁴, R⁵, R⁶, R¹², R¹³, R¹⁴ and R¹⁶ are hydrogen and A is—CH₂—, R¹⁴ is not

wherein

indicates the bond to the phenyl ring, when R⁴, R⁶, R¹², R¹⁵ and R¹⁶ arehydrogen, A is —CH₂, and R⁵ is thiophen-3-yl, R¹³ and R¹⁴ are not both—OH; and when R⁵, R⁶, R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen and A is —S—,R¹⁴ is not —CH₃; and when R¹⁴ is —N(CH₃)₂, R⁴, R⁶, R¹², R¹³, R¹⁵ and R¹⁶are hydrogen, and A is —CH₂—, then R⁵ is not 3-hydroxy-phenyl;

wherein

indicates the bond to the 5-position of the 7-azaindole ring. In furtherembodiments, when L is —O—, R²⁴ is not H or CH₃; and when L is —OCH₂—,R²⁴ is not H. In some embodiments, one of R¹², R¹³, R¹⁵, and R¹⁶ isother than hydrogen and the others are hydrogen. In some embodiments, atleast one of R¹², R¹³, R¹⁵, and R¹⁶ are other than hydrogen. In someembodiments, two of R¹², R¹³, R¹⁵, and R¹⁶ are other than hydrogen andthe others are hydrogen. In some embodiments, at least two of R¹², R¹³,R¹⁵, and R¹⁶ are other than hydrogen. In a some embodiments, at leastthree of R¹², R¹³, R¹⁵, and R¹⁶ are other than hydrogen. In someembodiments, R¹², R¹³, R¹⁵, and R¹⁶ are other than hydrogen. In someembodiments, one of R¹², R¹³, R¹⁵ and R¹⁶ is hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio, and theothers of R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, anytwo of R¹², R¹³, R¹⁵ and R¹⁶ is hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio and the remaining of R¹²,R¹³, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, R¹⁴ is —OR²⁴, whereR²⁴ is optionally substituted C₂₋₆ alkyl, optionally substituted loweralkenyl, optionally substituted lower alkynyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R¹⁴ is—O-alk-R²⁴, where R²⁴ is optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl. In some embodiments, R¹⁴ is —SR²⁴, where R²⁴ ishydrogen, optionally substituted lower alkyl, optionally substitutedlower alkenyl, optionally substituted lower alkynyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl, orR¹⁴ is —S-alk-R²⁴, where R²⁴ is optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl. In some embodiments, R¹⁴ is —NHR²⁴,where R¹⁴ is hydrogen, optionally substituted lower alkyl, optionallysubstituted lower alkenyl, optionally substituted lower alkynyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, or R¹⁴ is —NH-alk-R²⁴, where R²⁴ is optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. In someembodiments, A is —CH₂— or —C(O)—. In some embodiments, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen. In some embodiments, R⁴ is otherthan hydrogen and R⁵ and R⁶ are hydrogen. In some embodiments, R⁶ isother than hydrogen and R⁴ and R⁵ are hydrogen. In some embodiments, Ais —CH₂—, R⁵ is other than hydrogen and R⁴ and R⁶ are hydrogen. In someembodiments, A is —CH₂, R⁵ is other than hydrogen and R⁵ and R⁶ arehydrogen. In some embodiments, A is —CH₂—, R⁶ is other than hydrogen andR⁴ and R⁵ are hydrogen. In some embodiments, A is —C(O)—, R⁵ is otherthan hydrogen and R⁴ and R⁶ are hydrogen. In some embodiments, A is—C(O)—, R⁴ is other than hydrogen and R⁵ and R⁶ are hydrogen. In someembodiments, A is —C(O)—, R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen.

In some embodiments of compounds of Formula II, R¹⁴ is —OR²⁴ where R²⁴is optionally substituted C₂₋₆ alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R¹⁴ is —SR²⁴ where R²⁴ ishydrogen, optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R¹⁴ is—NHR²⁴, where R²⁴ is hydrogen, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl. In some embodiments, any one of R¹², R¹³, R¹⁵ and R¹⁶ ishydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen. Insome embodiments, two of R¹², R¹³, R¹⁵ and R¹⁶ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining two of R¹², R¹³R¹⁵ and R¹⁶ are hydrogen. Insome embodiments, R¹² is hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio and R¹³, R¹⁵ and R¹⁶ arehydrogen. In some embodiments, A is —CH₂— or —C(O)—. In someembodiments, R⁵ is other than hydrogen and R⁴ and R⁶ are hydrogen. Insome embodiments, R⁴ is other than hydrogen and R⁵ and R⁶ are hydrogen.In some embodiments, R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen. In some embodiments, A is —CH₂—, R⁵ is other than hydrogen andR⁴ and R⁶ are hydrogen. In some embodiments, A is —CH₂—, R⁴ is otherthan hydrogen and R⁵ and R⁶ are hydrogen. In some embodiments, A is—CH₂—, R⁶ is other than hydrogen and R⁴ and R⁵ are hydrogen. In someembodiments, A is —C(O)—, R⁵ is other than hydrogen and R⁴ and R⁶ arehydrogen. In some embodiments, A is —C(O)—, R⁴ is other than hydrogenand R⁵ and R⁶ are hydrogen. In some embodiments. A is —C(O)—, R⁶ isother than hydrogen and R⁴ and R⁵ are hydrogen.

In some embodiments of compounds of Formula II, R¹⁴ is -LR²⁴, where L is—NR²⁵-(alk)_(b)-, —C(O)NR²⁵-(alk)_(b)-, —OC(O)NR²⁵-(alk)_(b)-,—OC(S)NR²⁵-(alk)_(b)-, —C(S)NR²⁵-(alk)_(b)-, —S(O)₂NR²⁵-(alk)_(b)-,—NR²⁵C(O)-(alk)_(b)-, —NR²⁵C(S)-(alk)_(b)-, —NR²⁵C(O)NR²⁵-(alk)_(b)-,—NR²⁵C(S)NR²⁵-(alk)_(b)-, —NR²⁵C(O)O-(alk)_(b)-, —NR²⁵C(S)O-(alk)_(b)-,—NR²⁵S(O)₂-(alk)_(b)-, or —NR²⁵S(O)₂NR²⁵-(alk)_(b)-, wherein b, alk andR²⁵ are as defined for Formula I, and R²⁴ is optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. In someembodiments, any one of R¹², R¹³, R¹⁵, and R¹⁶ is other than hydrogenand the remaining of R¹², R¹³, R¹⁵, and R¹⁶ are hydrogen. In someembodiments, at least one of R¹², R¹³, R¹⁵, and R¹⁶ are other thanhydrogen. In some embodiments, any two of R¹², R¹³, R¹⁵, and R¹⁶ areother than hydrogen and the remaining of R¹², R¹³, R¹⁵, and R¹⁶ arehydrogen. In some embodiments, at least two of R¹², R¹³, R¹⁵ and R¹⁶ areother than hydrogen. In a some embodiments, at least three of R¹², R¹³,R¹⁵, and R¹⁶ are other than hydrogen. In a some embodiments, R¹², R¹³,R¹⁵, and R¹⁶ are other than hydrogen. In some embodiments, any one ofR¹², R¹³, R¹⁵ and R¹⁶ is hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio, and the remaining of R¹²,R¹³, R¹⁵, and R¹⁶ are hydrogen. In some embodiments, two of R¹², R¹³,R¹⁵ and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio and the others of R¹²,R¹³, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, A is selected from—CH₂— and —C(O)—. In some embodiments, R⁵ is other than hydrogen and R⁴and R⁶ are hydrogen. In some embodiments, R⁴ is other than hydrogen andR⁵ and R⁶ are hydrogen. In some embodiments, R⁶ is other than hydrogenand R⁴ and R⁵ are hydrogen. In some embodiments, A is —CH₂—, R⁵ is otherthan hydrogen and R⁴ and R⁶ are hydrogen. In some embodiments, A is—CH₂—, R⁴ is other than hydrogen and R⁵ and R⁶ are hydrogen. In someembodiments, A is —CH₂—, R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen. In some embodiments, A is —C(O)—, R⁴ is other than hydrogenand R⁴ and R⁶ are hydrogen. In some embodiments, A is —C(O)—, R⁶ isother than hydrogen and R⁴ and R⁶ are hydrogen. In some embodiments, Ais —C(O)—, R⁶ is other than hydrogen and R⁴ and R⁵ are hydrogen.

In some embodiments of any of the above embodiments of compounds ofFormula II wherein R¹⁴ is -LR²⁴, -LR²⁴ is not —NH₂, —OH, —OCH₃,—N(CH₃)₂, or

wherein

indicates the bond to the phenyl ring.

In some embodiments of compounds of Formula II, R¹³ and R¹⁵ are halogen,optionally fluoro substituted lower alkyl, —OR²⁴, where R²⁴ isoptionally substituted C₂₋₆ alkyl, optionally substituted lower alkenyl,optionally substituted lower alkynyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, —O-alk-R²⁴, where R²⁴ is optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl,—SR²⁴, where R²⁴ is hydrogen, optionally substituted lower alkyl,optionally substituted lower alkenyl, optionally substituted loweralkynyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, —S-alk-R²⁴, where R²⁴ is optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl, —NHR²⁴, where R²⁴ is hydrogen,optionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted lower alkynyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or —NH-alk-R²⁴,where R²⁴ is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl. In some embodiments, at least one of R¹², R¹⁴ and R¹⁶ isother than hydrogen. In some embodiments, at least two of R¹², R¹⁴ andR¹⁶ are other than hydrogen. In some embodiments, R¹², R¹⁴ and R¹⁶ areother than hydrogen. In some embodiments, any one of R¹², R¹⁴ and R¹⁶ ishydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹⁴ and R¹⁶ are hydrogen. In someembodiments, any two of R¹², R¹⁴ and R¹⁶ are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹⁴ and R¹⁶ is hydrogen. In someembodiments, R¹², R¹⁴ and R¹⁶ are independently hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, A is —CH₂— or —C(O)—. In some embodiments, R⁵ is other thanhydrogen and R⁴ and R⁶ are hydrogen. In some embodiments, R⁴ is otherthan hydrogen and R⁵ and R⁶ are hydrogen. In some embodiments, R⁶ isother than hydrogen and R⁴ and R⁵ are hydrogen. In some embodiments, Ais —CH₂—, R⁵ is other than hydrogen and R⁴ and R⁶ are hydrogen. In someembodiments, A is —CH₂—, R⁴ is other than hydrogen and R⁵ and R⁶ arehydrogen. In some embodiments, A is —CH₂—, R⁶ is other than hydrogen andR⁴ and R⁵ are hydrogen. In some embodiments, A is —C(O)—, R⁵ is otherthan hydrogen and R⁴ and R⁶ are hydrogen. In some embodiments, A is—C(O)—, R⁴ is other than hydrogen and R⁵ and R⁶ are hydrogen. In someembodiments, A is —C(O)—, R⁶ is other than hydrogen and R⁴ and R⁵ arehydrogen.

The compounds of Formula II, and all sub-embodiments detailed herein,may be used to treat a subject suffering from or at risk for any of theprotein kinase mediated diseases or conditions contemplated herein.

In some embodiments, compounds of Formula II have the structureaccording to the following sub-generic structure Formula IIa:

all salts, prodrugs, tautomers and isomers thereof, wherein A, R⁴, R⁵,R⁶, R¹², R¹⁶ and R²⁴ are as defined for Formula II, provided, however,that when A is C(O), R⁴, R⁵, R⁶, and R¹² are hydrogen and R¹⁶ is fluoro,then R²⁴ is not CH₃.

In some embodiments of compounds of Formula IIa, A is —CH₂— or —C(O)—.

In other embodiments of compounds of Formula IIa, A is —CH₂— or —C(O)—and R¹² and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio; in further embodiments,R¹² and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted C₁₋₃alkyl, optionally fluoro substituted C₁₋₃alkoxy, oroptionally fluoro substituted C₁₋₃alkylthio. In some embodiments, A is—CH₂— or —C(O)—, and R¹² and R¹⁶ are independently halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio; in furtherembodiments, R¹² and R¹⁶ are independently halogen, optionally fluorosubstituted C₁₋₃alkyl, optionally fluoro substituted C₁₋₃alkoxy, oroptionally fluoro substituted C₁₋₃alkylthio.

In other embodiments of compounds of Formula IIa, A is —CH₂—, R¹² ishydrogen and R¹⁶ is halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio; in further embodiments, R¹⁶ is halogen,optionally fluoro substituted C₁₋₃alkyl, optionally fluoro substitutedC₁₋₃alkoxy, or optionally fluoro substituted C₁₋₃alkylthio. In someembodiments, A is —CH₂—, R¹⁶ is hydrogen and R¹² is halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio; in furtherembodiments, R¹² is halogen, optionally fluoro substituted C₁₋₃alkyl,optionally fluoro substituted C₁₋₃alkoxy, or optionally fluorosubstituted C₁₋₃alkylthio.

In some embodiments of compounds of Formula IIa, A is —CH₂— and R¹² andR¹⁶ are independently halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio; in further embodiments, R¹² and R¹⁶ areindependently halogen, optionally fluoro substituted C₁₋₃alkyl,optionally fluoro substituted C₁₋₃alkoxy, and optionally fluorosubstituted C₁₋₃alkylthio.

In other embodiments of compounds of Formula IIa, A is —C(O)—, R¹² ishydrogen and R¹⁶ is halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio; in further embodiments, R¹⁶ is halogen,optionally fluoro substituted C₁₋₃alkyl, optionally fluoro substitutedC₁₋₃alkoxy, or optionally fluoro substituted C₁₋₃alkylthio. In someembodiments, A is —C(O)—, R¹⁶ is hydrogen and R¹² is halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio; in furtherembodiments, R¹² is halogen, optionally fluoro substituted C₁₋₃alkyl,optionally fluoro substituted C₁₋₃alkoxy, or optionally fluorosubstituted C₁₋₃alkylthio.

In some embodiments of compounds of Formula IIa, A is —C(O)— and R¹² andR¹⁶ are independently halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio; in further embodiments, R¹² and R¹⁶ areindependently hydrogen, halogen, optionally fluoro substitutedC₁₋₁₃alkyl, optionally fluoro substituted C₁₋₃alkoxy, or optionallyfluoro substituted C₁₋₃alkylthio.

In some embodiments of any of the above embodiments of compounds ofFormula IIa, R⁴ and R⁶ are hydrogen, or R⁵ and R⁶ are hydrogen, or R⁴and R⁵ are hydrogen.

In some embodiments of any of the above embodiments of compounds ofFormula IIa, R²⁴ is substituted methyl, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; in further embodiments, R²⁴ is C, lower alkyl, aryl orheteroaryl, wherein aryl and heteroaryl are optionally substituted withhalogen, lower alkyl or lower alkoxy; in further embodiments, R²⁴ isn-propyl, i-propyl, or phenyl, wherein phenyl is optionally substitutedwith halogen, lower alkyl or lower alkoxy.

In some embodiments, compounds of Formula II have the structureaccording to the following sub-generic structure Formula IIb:

all salts, prodrugs, tautomers and isomers thereof, wherein A, R⁴, R⁵,R⁶, R¹², R¹⁴, R¹⁵ and R¹⁶, are as defined for Formula II, R²⁸ ishydrogen, lower alkyl, or lower alkyl substituted with fluoro, hydroxyl,lower alkoxy, thiol, lower alkylthio, or —NR⁸R⁹, wherein R⁸ and R⁹ areas defined for Formula I, provided, however, that when R²⁸ issubstituted lower alkyl, any substitution of the alkyl carbon bound tothe nitrogen of NR²⁸ is fluoro, and R²⁹ is hydrogen, optionallysubstituted lower alkyl, optionally substituted lower alkenyl, provided,however, that nitrogen of NR²⁹ is not bound to any alkene carbonthereof, optionally substituted lower alkynyl, provided, however, thatnitrogen of NR²⁹ is not bound to any alkyne carbon thereof, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl, orR²⁸ and R²⁹ combine with the nitrogen to which they are attached formoptionally substituted 5-7 membered heterocycloalkyl or optionallysubstituted 5 or 7 membered nitrogen containing heteroaryl. In someembodiments of compounds of Formula IIb, A is —CH₂— or —C(O)—, R¹², R¹⁴,R¹⁵, and R¹⁶ are independently hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio, R²⁸ is hydrogen or loweralkyl and R²⁹ is optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl, or R²⁸ and R²⁹ combine with the nitrogen towhich they are attached form optionally substituted 5-7 memberedheterocycloalkyl or optionally substituted 5 or 7 membered nitrogencontaining heteroaryl.

In some embodiments of compounds of Formula IIb, A is —CH₂—, one of R¹²,R¹⁴, R¹⁵ and R¹⁶ is halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio and the remaining of R¹², R¹⁴, R¹⁵ and R¹⁶are hydrogen.

In other embodiments of compounds of Formula IIb, A is —CH₂—. R¹², R¹⁴and R¹⁵ are hydrogen and R¹⁶ is halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio.

In other embodiments of compounds of Formula IIb, A is —CH₂—, R¹⁴, R¹⁵and R¹⁶ are hydrogen and R¹² is halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio.

In some embodiments of compounds of Formula IIb, A is —CH₂—, two of R¹²,R¹⁴, R¹⁵ and R¹⁶ are independently halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio and the other two of R¹²,R¹⁴, R¹⁵ and R¹⁶ are hydrogen.

In some embodiments of compounds of Formula IIb, A is —CH₂—, R¹⁴ and R¹⁵are hydrogen and R¹² and R¹⁶ are independently halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio.

In some embodiments of compounds of Formula IIb, A is —C(O)—, one ofR¹², R¹⁴, R¹⁵ and R¹⁶ is halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio and the others of R¹², R¹⁴, R¹⁵ and R¹⁶ arehydrogen.

In some embodiments of compounds of Formula IIb, A is —C(O)—, R¹², R¹⁴and R¹⁵ are hydrogen and R¹⁶ is halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio.

In some embodiments of compounds of Formula IIb, A is —C(O)—, R¹⁴, R¹⁵and R¹⁶ are hydrogen and R¹² is halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio.

In some embodiments of compounds of Formula IIb, A is —C(O)—, two ofR¹², R⁴, R¹⁵ and R¹⁶ are independently halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio and the other two of R¹²,R¹⁴, R¹⁵ and R¹⁶ are hydrogen.

In some embodiments of compounds of Formula IIb, A is —C(O)—, R¹⁴ andR¹⁵ are hydrogen and R¹² and R¹⁶ are independently halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio.

In some embodiments of any of the above embodiments of compounds ofFormula IIb, R⁴ and R⁶ are hydrogen, or R⁵ and R⁶ are hydrogen, or R⁴and R⁵ are hydrogen. In some embodiments of any of the above embodimentsof compounds of Formula IIb, R²⁸ and R²⁹ are both lower alkyl, or R²⁸and R²⁹ combine with the nitrogen to which they are attached to formoptionally substituted 5-7 membered heterocycloalkyl, further whereinthe heterocycloalkyl is pyrrolidine, piperidine, piperazine ormorpholine.

In some embodiments, compounds of Formula II have the structureaccording to the following sub-generic structures Formulae IIc, IId,IIe, IIf, or IIg:

all salts, prodrugs, tautomers and isomers thereof, wherein A, X, R⁴,R⁵, R⁶, R¹², R¹⁴, R¹⁵, R¹⁶ and R²⁴ are as defined for Formula II. Insome embodiments of compounds of Formulae IIe, IId, IIe, IIf, or IIg, Ais —CH₂— or —C(O)—. In some embodiments, any one of R¹², R¹⁴, R¹⁵, andR¹⁶ is other than hydrogen. In some embodiments, any two of R¹², R¹⁴,R¹⁵, and R¹⁶ are other than hydrogen. In some embodiments, any three ofR¹², R¹⁴, R¹⁵, and R¹⁶ are other than hydrogen. In some embodiments,R¹², R¹⁴, R¹⁵, and R¹⁶ are other than hydrogen. In some embodiments, Ais —CH₂— or —C(O)— and R¹², R¹⁴, R¹⁵, and R¹⁶ are independentlyhydrogen, halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, A is —CH₂—, any one of R¹², R¹⁴, R¹⁵ andR¹⁶ is halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen. Insome embodiments, A is —CH₂—, R¹², R¹⁴ and R¹⁵ are hydrogen and R¹⁶ ishalogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, A is —CH₂—, R¹⁴, R¹⁵ and R¹⁶ arehydrogen and R¹² is halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio. In some embodiments, A is —CH₂—, any two ofR¹², R¹⁴, R¹⁵ and R¹⁶ are independently halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio and the remaining two ofR¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, A is —CH₂—, R¹⁴and R¹⁵ are hydrogen and R¹² and R¹⁶ are independently halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, A is —C(O)—, any one of R¹², R¹⁴. R¹⁵ and R¹⁶ is halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio and theremaining of R¹², R¹⁴, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, Ais —C(O)—, R¹², R¹⁴ and R¹⁵ are hydrogen and R¹⁶ is halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, A is —C(O)—, R¹⁴, R¹⁵ and R¹⁶ are hydrogen and R¹² ishalogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, A is —C(O)—, any two of R¹², R¹⁴, R¹⁵and R¹⁶ are independently halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio and the remaining two of R¹², R¹⁴, R¹⁵ andR⁶ are hydrogen. In some embodiments, A is —C(O)—, R¹⁴ and R¹⁵ arehydrogen and R¹² and R¹⁶ are independently halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments ofany of the above embodiments of compounds of Formula IIc, IId, IIe, IIf,and IIg, R⁴ and R⁶ are hydrogen or R⁵ and R⁶ are hydrogen, or R⁴ and R⁵are hydrogen.

In some embodiments, compounds of Formula II have the structureaccording to the following sub-generic structure Formula IIh:

salts, prodrugs, tautomers and isomers thereof, wherein A, R⁵, R¹², R¹³,R¹⁵, R¹⁶ and R²⁴ are as defined for Formula II, and Z is —O—, —S— or—NH—. In some embodiments of compounds of Formula IIh, R²⁴ is hydrogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl. In some embodiments, R²⁴ is hydrogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl and at least one of R¹², R¹³, R¹⁵ andR¹⁶ is halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the others of R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen; infurther embodiments, R¹³ is halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio and R¹², R¹⁵ and R¹⁶ are hydrogen; infurther embodiments, A is —CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIh, Z is —O— or —NH—, R²⁴is hydrogen, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or lower alkyl optionally substituted with optionallysubstituted aryl or optionally substituted heteroaryl, and at least oneof R¹², R¹³, R¹⁵ and R¹⁶ is halogen, optionally fluoro substituted loweralkyl, or optionally fluoro substituted lower alkoxy and the others ofR¹², R¹³, R¹⁵ and R¹⁶ are hydrogen; in further embodiments, R¹³ ishalogen, optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy and R¹², R¹⁵ and R¹⁶ are hydrogen; in furtherembodiments, A is —CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIh, Z is —O— or —NH—, R²⁴is hydrogen, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or lower alkyl optionally substituted with optionallysubstituted aryl or optionally substituted heteroaryl, R¹³ is halogen,optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy and one of R¹², R¹⁵ and R¹⁶ is halogen,optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy and the others of R¹², R¹⁵ and R¹⁶ arehydrogen; in further embodiments, A is —CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIh, Z is —O— or —NH—, R²⁴is hydrogen, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or lower alkyl optionally substituted with optionallysubstituted aryl or optionally substituted heteroaryl, R¹³ is halogen,optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy and two of R¹², R¹⁵ and R¹⁶ are independentlyhalogen, optionally fluoro substituted lower alkyl, or optionally fluorosubstituted lower alkoxy and the other of R¹², R¹⁵ and R¹⁶ is hydrogen;in further embodiments, A is —CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIh, Z is —O— or —NH—, R²⁴is hydrogen, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or lower alkyl optionally substituted with optionallysubstituted aryl or optionally substituted heteroaryl, R¹², R¹³, R¹⁵ andR¹⁶ are independently hydrogen, halogen, optionally fluoro substitutedlower alkyl, or optionally fluoro substituted lower alkoxy; in furtherembodiments, A is —CH₂— or —C(O)—.

In some embodiments, compounds of Formula II have the structureaccording to the following sub-generic structures Formulae IIi, IIj,IIk, IIm, or IIn:

all salts, prodrugs, tautomers and isomers thereof, wherein A, X, R⁴,R⁵, R⁶, R¹², R¹³. R¹⁵, R¹⁶ and R¹⁴ are as defined for Formula II. Insome embodiments of compounds of Formulae II, IIj, IIk, IIm, or IIn, Ais —CH₂— or —C(O)—. In some embodiments, one of R¹², R¹³, R¹⁵, and R¹⁶is other than hydrogen. In some embodiments, two of R¹², R¹³, R¹⁵ andR¹⁶ are other than hydrogen. In one embodiment, three of R¹², R¹³, R¹⁵,and R¹⁶ are other than hydrogen. In some embodiments, R¹², R¹³, R¹⁵, andR¹⁶ are other than hydrogen.

In some embodiments of compounds of Formulae IIi, IIj, IIk, IIm, or IIn,A is —CH₂— or —C(O)—, R¹², R¹³, R¹⁵, and R¹⁶ are independently hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, A is —CH₂—, any one of R¹², R¹³, R¹⁵ andR¹⁶ is halogen, optionally fluoro substituted lower alkyl, optionallyfluoro substituted lower alkoxy, or optionally fluoro substituted loweralkylthio and the remaining of R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen. Insome embodiments, A is —CH₂—, R¹³, R¹⁵ and R¹⁶ are hydrogen and R¹² ishalogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, A is —CH₂—, R¹², R¹⁵ and R¹⁶ arehydrogen and R¹³ is halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio. In some embodiments, A is —CH₂—, any two ofR¹², R¹³, R¹⁵ and R¹⁶ are independently halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio and the remaining two ofR¹², R¹³, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, A is —CH₂—, R¹⁵and R¹⁶ are hydrogen and R¹² and R¹³ are independently halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, A is —CH₂—, R¹³ and R¹⁶ are hydrogen and R¹² and R¹⁵ areindependently halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio. In some embodiments, A is —CH₂—, R¹³ andR¹⁵ are hydrogen and R¹² and R¹⁶ are independently halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, A is —CH₂—, R¹² and R¹⁶ are hydrogen and R¹³ and R¹⁵ areindependently halogen, optionally fluoro substituted lower alkyl,optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio.

In some embodiments of compounds of Formulae IIi, IIj, IIk, IIm, or IIn,A is —C(O)—, any one of R¹², R¹³, R¹⁵ and R¹⁶ is halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio and theremaining of R¹², R¹³, R¹⁵ and R¹⁶ are hydrogen. In some embodiments, Ais —C(O)—, R¹³, R¹⁵ and R¹⁶ are hydrogen and R¹² is halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments, A is —C(O)—, R¹², R¹⁵ and R¹⁶ are hydrogen and R¹³ ishalogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, A is —C(O)—, two of R¹², R¹³, R¹⁵ andR¹⁶ are independently halogen, optionally fluoro substituted loweralkyl, optionally fluoro substituted lower alkoxy, or optionally fluorosubstituted lower alkylthio and the remaining two of R¹², R¹³, R¹⁵ andR¹⁶ are hydrogen. In some embodiments, A is —C(O)—, R¹⁵ and R¹⁶ arehydrogen and R¹² and R¹³ are independently halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio. In some embodiments, A is—C(O)—, R¹³ and R¹⁶ are hydrogen and R¹² and R¹⁵ are independentlyhalogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio. In some embodiments, A is —C(O)—, R¹³ and R¹⁵ are hydrogenand R¹² and R¹⁶ are independently halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio. In some embodiments, A is —C(O)—,R¹² and R¹⁶ are hydrogen and R¹³ and R¹⁵ are independently halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio. In someembodiments of any of the above embodiments of compounds of Formula IIa,R⁴ and R⁶ are hydrogen or R⁵ and R⁶ are hydrogen, or R⁴ and R⁵ arehydrogen.

In some embodiments, compounds of Formula II have the structureaccording to the following sub-generic structure Formula IIo:

all salts, prodrugs, tautomers and isomers thereof, wherein A, R⁵, R¹²,R¹⁴, R¹⁶ and R²⁴ are as defined for Formula II, where each R²⁴ isselected independently, and each Z is independently —O—, —S— or —NH—. Insome embodiments of compounds of Formula IIo, each R²⁴ is independentlyhydrogen, optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. In someembodiments, each R²⁴ is independently hydrogen, optionally substitutedlower alkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl and R¹², R¹⁴ and R¹⁶ are hydrogen.

In some embodiments of compounds of Formula IIo, each R²⁴ isindependently hydrogen, optionally substituted lower alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl and atleast one of R¹², R¹⁴ and R¹⁶ is hydrogen, halogen, optionally fluorosubstituted lower alkyl, optionally fluoro substituted lower alkoxy, oroptionally fluoro substituted lower alkylthio, and the others of R¹²,R¹⁴ and R¹⁶ are hydrogen; in further embodiments, R¹² is hydrogen,halogen, optionally fluoro substituted lower alkyl, optionally fluorosubstituted lower alkoxy, or optionally fluoro substituted loweralkylthio and R¹⁴ and R¹⁶ are hydrogen; in further embodiments, A is—CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIo, each R²⁴ isindependently hydrogen, optionally substituted lower alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl and atleast two of R¹², R¹⁴ and R¹⁶ are independently hydrogen, halogen,optionally fluoro substituted lower alkyl, optionally fluoro substitutedlower alkoxy, or optionally fluoro substituted lower alkylthio, and theother of R¹², R¹⁴ and R¹⁶ is hydrogen; in further embodiments, R¹² andR¹⁶ are independently hydrogen, halogen, optionally fluoro substitutedlower alkyl, optionally fluoro substituted lower alkoxy, or optionallyfluoro substituted lower alkylthio and R¹⁴ is hydrogen; in furtherembodiments, A is —CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIo, L is —O— or —NH—, eachR²⁴ is independently hydrogen, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl, R¹² and R¹⁶ are independently hydrogen, halogen, optionallyfluoro substituted lower alkyl, optionally fluoro substituted loweralkoxy, or optionally fluoro substituted lower alkylthio and R¹⁴ ishydrogen; in further embodiments, A is —CH₂— or —C(O)—.

The compounds of Formulae IIa-IIo, and all sub-embodiments detailedherein, may be used to treat a subject suffering from or at risk for anyof the protein kinase mediated diseases or conditions contemplatedherein.

In some embodiments, compounds of Formula I have the structure accordingto the following sub-generic structure Formula III:

all salts, prodrugs, tautomers, and isomers thereof,

wherein:

Q has a structure selected from the group consisting of

in which

indicates the attachment point of Q to A of Formula III;

-   -   Z₂ is N or CR¹²; Z₄ is N or CR¹⁴; Z₅ is N or CR¹⁵; Z₆ is N or        CR¹⁶;    -   L₂ is selected from the group consisting of        —(CR¹⁰R¹¹)_(p)—NR²⁵—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—O—(CR¹⁰R¹¹)_(q)—, —(CR¹⁰R¹¹)_(p)—S(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—C(O)—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—C(S)—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—S(O)₂—(CR¹⁰R¹¹)_(p)—,        —(CR¹⁰R¹¹)_(p)—S(O)—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—C(O)NR²⁵—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—C(S)NR²⁵—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—S(O)₂NR²⁵—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—NR²⁵C(O)—(CR¹⁰R¹¹)_(q)—,        —(CR¹⁰R¹¹)_(p)—NR²⁵C(S)—(CR¹⁰R¹¹)_(q)—, and        —(CR¹⁰R¹¹)_(p)—NR²⁵S(O)₂—(CR¹⁰R¹¹)_(q)—;    -   p and q are independently 0, 1, or 2 provided, however, that at        least one of p and q is 0;    -   s is 1 or 2;    -   X is O or S;    -   A is selected from the group consisting of —O—, —S—,        —CR^(a)R^(b)—, —NR¹—, —C(O)—, —C(S)—, —S(O)—, and —S(O)₂—;    -   R^(a) and R^(b) at each occurrence are independently selected        from the group consisting of hydrogen, fluoro, —OH, —NH₂, lower        alkyl, lower alkoxy, lower alkylthio, mono-alkylamino,        di-alkylamino, and —NR⁸R⁹, wherein the alkyl chain(s) of lower        alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or        di-alkylamino are optionally substituted with one or more        substituents selected from the group consisting of fluoro, —OH,        —NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino, provided, however, that any        substitution of the alkyl chain carbon bound to O of alkoxy, S        of thioalkyl or N of mono- or di-alkylamino is fluoro; or    -   R^(a) and R^(b) combine to form a 3-7 membered monocyclic        cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein        the monocyclic cycloalkyl or monocyclic heterocycloalkyl are        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)R⁷,        —C(S)R⁷, —S(O)₂R⁷, —C(O)NHR⁷, —C(S)NHR⁷, and —S(O)₂NHR⁷, wherein        lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, —OH,        —NH₂, lower alkoxy, lower alkylthio, mono-alkylamino,        di-alkylamino, and —NR⁸R⁹, wherein the alkyl chain(s) of lower        alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of        mono- or di-alkylamino is fluoro, further provided that when R¹        is lower alkyl, any substitution on the lower alkyl carbon bound        to the N of —NR¹— is fluoro, and wherein cycloalkyl,        heterocycloalkyl, aryl or heteroaryl are optionally substituted        with one or more substituents selected from the group consisting        of halogen, —OH, —NH₂, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino;    -   R⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein        lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, —OH,        —NH₂, lower alkoxy, lower alkylthio, mono-alkylamino,        di-alkylamino, and —NR⁸R⁹, provided, however, that any        substitution of the alkyl carbon bound to the N of —C(O)NHR⁷,        —C(S)NHR⁷ or —S(O)₂NHR⁷ is fluoro, wherein the alkyl chain(s) of        lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino        are optionally substituted with one or more substituents        selected from the group consisting of fluoro, —OH, —NH₂, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of        mono- or di-alkylamino is fluoro, and wherein cycloalkyl,        heterocycloalkyl, aryl and heteroaryl are optionally substituted        with one or more substituents selected from the group consisting        of halogen, —OH, —NH₂, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino;    -   R⁴, R⁵, R⁶, R¹², R¹⁴, R¹⁵, R¹⁶, R⁴², R⁴³, R⁴⁵, R⁴⁶ and R⁴⁷ are        independently selected from the group consisting of hydrogen,        halogen, optionally substituted lower alkyl, optionally        substituted lower alkenyl, optionally substituted lower alkynyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, optionally        substituted heteroaryl, —CN, —NO₂, —CR^(a)R^(b)R²⁶, and -LR²⁶;    -   L at each occurrence is independently selected from the group        consisting of -(alk)_(a)-S-(alk)_(b)-, -(alk)_(a)-O-(alk)_(b)-,        -(alk)_(a)-NR²⁵-(alk)_(b)-, -(alk)_(a)-C(O)-(alk)_(b)-,        -(alk)_(a)-C(S)-(alk)_(b)-, -(alk)_(a)-S(O)-(alk)_(b)-,        -(alk)_(a)-S(O)₂-(alk)_(b)-, -(alk)_(a)-OC(O)-(alk)_(b)-,        -(alk)_(a)-C(O)O-(alk)_(b)-, -(alk)_(a)-OC(S)-(alk)_(b)-,        -(alk)_(a)-C(S)O-(alk)_(b)-, -(alk)_(a)-C(O)NR²⁵-(alk)_(b)-,        -(alk)_(a)-C(S)NR²⁵-(alk)_(b)-, -(alk)_(a)-S(O)₂NR²⁵-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(O)-(alk)_(b)-, -(alk)_(a)-NR²⁵(S)-(alk)_(b)-,        -(alk)_(a)-NR²⁵S(O)₂-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(O)O-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(S)O-(alk)_(b)-,        -(alk)_(a)-OC(O)NR²⁵-(alk)_(b)-,        -(alk)_(a)-OC(S)NR²⁵-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(O)NR²⁵-(alk)_(b)-,        -(alk)_(a)-NR²⁵C(S)NR²⁵-(alk)_(b)-, and        -(alk)_(a)-NR²⁵S(O)₂NR²⁵-(alk)_(b)-;    -   a and b are independently 0 or 1;    -   alk is C₁₋₃ alkylene or C₁₋₃ alkylene substituted with one or        more substituents selected from the group consisting of fluoro,        —OH, —NH₂, lower alkyl, lower alkoxy, lower alkylthio,        mono-alkylamino, di-alkylamino, and —NR⁸R⁹, wherein lower alkyl        or the alkyl chain(s) of lower alkoxy, lower alkylthio,        mono-alkylamino or di-alkylamino are optionally substituted with        one or more substituents selected from the group consisting of        fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino and cycloalkylamino, provided,        however, that any substitution of the alkyl chain carbon bound        to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is        fluoro;    -   R²⁵ at each occurrence is independently selected from the group        consisting of hydrogen, optionally substituted lower alkyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, and optionally        substituted heteroaryl;    -   R²⁶ at each occurrence is independently selected from the group        consisting of hydrogen, provided, however, that hydrogen is not        bound to any of S(O), S(O)₂, C(O) or C(S) of L, optionally        substituted lower alkyl, optionally substituted lower alkenyl,        provided, however, that when R²⁶ is optionally substituted lower        alkenyl, no alkene carbon thereof is bound to N, S, O, S(O),        S(O)₂, C(O) or C(S) of L, optionally substituted lower alkynyl,        provided, however, that when R²⁶ is optionally substituted lower        alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O),        S(O), C(O) or C(S) of L, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, and optionally substituted heteroaryl;    -   R¹⁰ and R¹¹ at each occurrence are independently selected from        the group consisting of hydrogen, fluoro, lower alkyl, and lower        alkyl optionally substituted with one or more substituents        selected from the group consisting of fluoro, —OH, —NH₂, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino; or    -   any two of R¹⁰ and R¹¹ on the same or adjacent carbon atoms        combine to form a 3-7 membered monocyclic cycloalkyl or 5-7        membered monocyclic heterocycloalkyl, and any others of R¹⁰ and        R¹¹ are independently selected from the group consisting of        hydrogen, fluoro, lower alkyl, and lower alkyl optionally        substituted with one or more substituents selected from the        group consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, and wherein the monocyclic cycloalkyl or        monocyclic heterocycloalkyl are optionally substituted with one        or more substituents selected from the group consisting of        halogen, —OH, —NH₂, lower alkyl, fluoro substituted lower alkyl,        lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,        fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino;    -   R⁸ and R⁹ combine with the nitrogen to which they are attached        to form a 5-7 membered heterocycloalkyl optionally substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, and fluoro substituted lower alkylthio;    -   R¹⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl and —OR¹⁸;    -   R³¹ and R³³ are independently selected from the group consisting        of optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted cycloalkyl, and optionally        substituted heterocycloalkyl;    -   R³⁶ is selected from the group consisting of substituted methyl,        optionally substituted C₂₋₆ alkyl, optionally substituted lower        alkenyl, provided, however, that when R³⁶ is optionally        substituted lower alkenyl, no alkene carbon thereof is bound to        the S(O)₂ of S(O)₂R³⁶, optionally substituted lower alkynyl,        provided, however, that when R³⁶ is optionally substituted lower        alkynyl, no alkyne carbon thereof is bound to the S(O)₂ of        S(O)₂R³⁶, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl, and —NR¹⁹R²⁰;    -   R¹⁹, R²⁰, R³⁴, R³⁵, R³⁷, and R³⁸ are independently selected from        the group consisting of hydrogen, optionally substituted lower        alkyl, optionally substituted lower alkenyl, provided, however,        that when R¹⁹, R²⁰, R³⁴, R³⁵, R³⁷, or R³⁸ is optionally        substituted lower alkenyl, no alkene carbon thereof is bound to        the N of NR¹⁹R²⁰, NR³⁴R³⁵ or NR³⁷R³⁸, optionally substituted        lower alkynyl, provided, however, that when R¹⁹, R²⁰, R³⁴, R³⁵,        R³⁷, or R³⁸ is optionally substituted lower alkynyl, no alkyne        carbon thereof is bound to the N of NR¹⁹R²⁰, NR³⁴R³⁵ or NR³⁷R³⁸,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl and optionally        substituted heteroaryl; or    -   R³⁴ and R³⁵ together with the nitrogen to which they are        attached form optionally substituted 5-7 membered        heterocycloalkyl or optionally substituted 5 or 7 membered        nitrogen containing heteroaryl; or    -   R³⁷ and R³⁸ together with the nitrogen to which they are        attached form optionally substituted 5-7 membered        heterocycloalkyl or optionally substituted 5 or 7 membered        nitrogen containing heteroaryl;    -   R³² is selected from the group consisting of hydrogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, and —OR¹⁸;    -   R⁸² is selected from hydrogen or lower alkyl; and    -   R¹⁸ is hydrogen or optionally substituted lower alkyl;    -   provided, however, that the compound is not        3-{3-[2-(tetrahydropyran-2-yloxy)-ethoxy]-benzyl}-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine,        which has the structure

or

-   -   4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-benzamide,        which has the structure

The compounds of Formula III, and all sub-embodiments detailed herein,may be used to treat a subject suffering from or at risk for any of theprotein kinase mediated diseases or conditions contemplated herein.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIa:

all salts, prodrugs, tautomers and isomers thereof, wherein A, L₂, Z₂,Z₆, R⁴, R⁵, R⁶, R¹⁵, R¹⁷ and R³¹ are as defined for Formula III.

In some embodiments of compounds of Formula IIIa. R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, more preferably —CH₂—, R¹⁷ is selected from the group consistingof hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkylchain of lower alkyl or lower alkoxy is optionally substituted with oneor more substituents selected from the group consisting of fluoro, —OH,—NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino andcycloalkylamino, provided, however, that any substitution on the alkylcarbon hound to the —O— of lower alkoxy is fluoro, and R¹⁵ is selectedfrom the group consisting of hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, and fluoro substituted loweralkoxy.

In some embodiments of compounds of Formula IIIa, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, R¹⁷ is selected from the group consisting of hydrogen, halogen,lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl orlower alkoxy is optionally substituted with one or more substituentsselected from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino,provided, however, that any substitution on the alkyl carbon bound tothe —O— of lower alkoxy is fluoro, R¹⁵ is selected from the groupconsisting of hydrogen, halogen, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy, Z₂ is N orCR¹², Z₆ is N or CR¹⁶, R¹² and R¹⁶ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, and fluoro substituted lower alkoxy, and R⁵is selected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, optionally substituted aryl, optionally substitutedheteroaryl, and NR²¹R²², wherein R²¹ is hydrogen or lower alkyl, and R²²is hydrogen, lower alkyl, optionally substituted aryl or optionallysubstituted heteroaryl, and wherein the alkyl chain of R⁵, R²¹, or R²²,when lower alkyl, or the alkyl chain of lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIb:

all salts, prodrugs, tautomers, and isomers thereof,

-   -   wherein:    -   A₁ is —O—, —CR⁴⁰R⁴¹—, —C(O)— or —NR⁴⁸—;    -   Z₁₂ is N or CR⁵²;    -   Z₁₆ is N or CR¹⁶;    -   R⁴⁰ and R⁴¹ are independently selected from the group consisting        of hydrogen, fluoro, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino; or    -   R⁴⁰ and R⁴¹ combine to form a 3-7 membered monocyclic cycloalkyl        or 5-7 membered monocyclic heterocycloalkyl, wherein the        monocyclic cycloalkyl or monocyclic heterocycloalkyl is        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   L₃ is selected from the group consisting of —NR⁴⁸—, —S—, —O—,        —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, —OCH(R⁴⁹)—, —C(O)NR⁴⁸—, —S(O)₂NR⁴⁸—,        —CH(R⁴⁹)NR⁴⁸—, —CH(R⁴⁹)O—, —CH(R⁴⁹)S—, —NR⁴⁸C(O)—, and        —NR⁴⁸S(O)₂—;    -   R⁵³ and R⁵⁵ are independently selected from the group consisting        of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the        alkyl chain of lower alkyl or lower alkoxy is optionally        substituted with fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino or        cycloalkylamino, provided, however, that any substitution on the        alkyl carbon bound to the —O— of lower alkoxy is fluoro;    -   R⁵² and R⁶ are independently selected from the group consisting        of hydrogen, halogen, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   R⁴⁹ is selected from the group consisting of hydrogen, lower        alkyl, and fluoro substituted lower alkyl;    -   Cy is selected from the group consisting of aryl, heteroaryl,        cycloalkyl, and heterocycloalkyl;    -   R³⁹ is selected from the group consisting of hydrogen, halogen,        lower alkyl, lower alkoxy, aryl, heteroaryl, and NR⁵⁰R⁵¹,        wherein the alkyl chain of lower alkyl or lower alkoxy is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino and        cycloalkylamino, and wherein aryl and heteroaryl are optionally        substituted with one or more independent substituents R²²;    -   R⁵⁰ is hydrogen or lower alkyl optionally substituted with one        or more substituents selected from the group consisting of        fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino and cycloalkylamino;    -   R⁵¹ is aryl or heteroaryl, wherein aryl and heteroaryl are        optionally substituted with one or more independent substituents        R⁷³;    -   R²³ at each occurrence is independently selected from the group        consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂,        —C(O)NH₂, —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —NR⁴⁸C(O)R⁵⁷, —NR⁴⁸S(O)₂R⁵⁷,        —S(O)₂R⁵⁷, —C(O)R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, —S(O)₂NR⁴⁸R⁵⁷,        halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl, wherein lower alkyl is optionally substituted with        one or more substituents selected from the group consisting of        fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R²³, or as substituents of lower alkyl, are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁵⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower        alkyl is optionally substituted with one or more substituents        selected from the group consisting of fluoro, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided,        however, that any substitution of the alkyl carbon bound to O,        S, or N of —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —C(O)OR⁵, —C(O)NR⁴⁸R⁵⁷, or        —S(O)₂NR⁴⁸R⁵⁷ is fluoro, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁵⁷ or as substituents of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl carbon bound to O, S, or N of —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸,        —C(O)OR⁵, —C(O)NR⁴⁸R⁵⁸, or —S(O)₂NR⁴⁸R⁵⁸ is fluoro;    -   R⁴⁸ at each occurrence is independently hydrogen or lower alkyl;        and    -   t is 0, 1, 2, or 3.

In some embodiments of compounds of Formula IIIb, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—, more preferably —CH₂—. In someembodiments, A₁ is —CR⁴⁰R⁴¹— or —C(O)—, preferably —CH₂— or —C(O)—, morepreferably —CH₂—, and R⁵³ and R⁵⁵ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, and fluoro substituted lower alkoxy. In someembodiments, L₃ is —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, or —OCH(R⁴⁹)—, preferably—OCH(R⁴⁹)—. In some embodiments, A₁ is —CR⁴⁰R⁴¹— or —C(O)—, preferably—CH₂— or —C(O)—, more preferably —CH₂—, and L₃ is —NR⁴⁸CH(R⁴⁹)—,—SCH(R⁴⁹)—, or —OCH(R⁴⁹)—, preferably —OCH(R⁴⁹)—.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIp:

all salts, prodrugs, tautomers, and isomers thereof,

-   -   wherein:    -   A₁ is —O—, —CR⁴⁰R⁴¹—, —C(O)— or —NR⁴⁸—;    -   Z₂₂ is N or CR²;    -   Z₂₆ is N or CR⁶⁶;    -   r is 0, 1, or 2;    -   R⁴⁰ and R⁴¹ are independently selected from the group consisting        of hydrogen, fluoro, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino; or    -   R⁴⁰ and R⁴¹ combine to form a 3-7 membered monocyclic cycloalkyl        or 5-7 membered monocyclic heterocycloalkyl, wherein the        monocyclic cycloalkyl or monocyclic heterocycloalkyl is        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   R⁶², R⁶³, R⁶⁵, and R⁶⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl and lower alkoxy,        wherein the alkyl chain of lower alkyl or lower alkoxy is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino and        cycloalkylamino, provided, however, that any substitution on the        alkyl carbon bound to the —O— of lower alkoxy is fluoro;    -   Cy is selected from the group consisting of aryl, heteroaryl,        cycloalkyl, and heterocycloalkyl;    -   R³⁹ is selected from the group consisting of hydrogen, halogen,        lower alkyl, lower alkoxy, aryl, heteroaryl, and NR⁵⁰R⁵¹,        wherein the alkyl chain of lower alkyl or lower alkoxy is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino and        cycloalkylamino, and wherein aryl and heteroaryl are optionally        substituted with one or more independent substituents R²³;    -   R⁵⁰ is hydrogen or lower alkyl optionally substituted with one        or more substituents selected from the group consisting of        fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino and cycloalkylamino;    -   R⁵¹ is aryl or heteroaryl, wherein aryl and heteroaryl are        optionally substituted with one or more independent substituents        R²³;    -   R²³ at each occurrence is independently selected from the group        consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂,        —C(O)NH₂, —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —NR⁴⁸C(O)R⁵⁷, —NR⁴⁸S(O)₂R⁵⁷,        —S(O)₂R⁵⁷, —C(O)R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, —S(O)₂NR⁴⁸R⁵⁷,        halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl, wherein lower alkyl is optionally substituted with        one or more substituents selected from the group consisting of        fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R²³, or as substituents of lower alkyl, are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR¹⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁵⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower        alkyl is optionally substituted with one or more substituents        selected from the group consisting of fluoro, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided,        however, that any substitution of the alkyl carbon bound to O,        S, or N of —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, or        —S(O)₂NR⁴⁸R⁵⁷ is fluoro, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁵, or as substituents of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl carbon bound to O, S, or N of —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸,        —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸, or —S(O)₂NR⁴⁸R⁵⁸ is fluoro;    -   R⁴⁸ at each occurrence is independently hydrogen or lower alkyl;        and    -   t is 0, 1, 2, or 3.

In some embodiments of compounds of Formula IIIp, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—. In some embodiments, A₁ is —CR⁴⁰R⁴¹or —C(O)—, preferably —CH₂— or —C(O)—, and R⁶², R⁶⁴, R⁶⁵ and R⁶⁶ areindependently selected from the group consisting of hydrogen, halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluorosubstituted lower alkoxy.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIc:

all salts, prodrugs, tautomers and isomers thereof, wherein A, s, Z₂,Z₆, R⁴, R⁵, R⁶, R¹⁵, R¹⁷, and R³² are as defined for Formula III.

In some embodiments of compounds of Formula IIIc, R⁴ and R⁶ arehydrogen, A is —O—. —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, more preferably —CH₂—, R¹⁷ is selected from the group consistingof hydrogen, halogen, lower alkyl and lower alkoxy, wherein the alkylchain of lower alkyl or lower alkoxy is optionally substituted with oneor more substituents selected from the group consisting of fluoro, —OH,—NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio,fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino andcycloalkylamino, provided, however, that any substitution on the alkylcarbon bound to the —O— of lower alkoxy is fluoro, and R¹⁵ is selectedfrom the group consisting of hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, and fluoro substituted loweralkoxy.

In some embodiments of compounds of Formula IIIc, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, R¹⁷ is selected from the group consisting of hydrogen, halogen,lower alkyl and lower alkoxy, wherein the alkyl chain of lower alkyl orlower alkoxy is optionally substituted with one or more substituentsselected from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino,provided, however, that any substitution on the alkyl carbon bound tothe —O— of lower alkoxy is fluoro, R¹⁵ is selected from the groupconsisting of hydrogen, halogen, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy, Z₂ is N orCR¹², Z₆ is N or CR¹⁶, R¹² and R¹⁶ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, and fluoro substituted lower alkoxy, and R⁵is selected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, optionally substituted aryl, optionally substitutedheteroaryl, and —NR²¹R²², wherein R²¹ is hydrogen or lower alkyl, andR²² is hydrogen, lower alkyl, optionally substituted aryl or optionallysubstituted heteroaryl, and wherein the alkyl chain of R⁵, R²¹ or R²²,when lower alkyl, or the alkyl chain of lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, further wherein R³²is optionally substituted lower alkyl or —OR¹⁸, where R¹⁸ is as definedfor Formula III.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIn:

all salts, prodrugs, tautomers and isomers thereof, wherein A, s, Z₂,Z₆, R⁵, R⁶, R¹⁵, and R³² are as defined for Formula III.

In some embodiments of compounds of Formula IIIn, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, more preferably —CH₂—, and R¹⁵ is selected from the groupconsisting of hydrogen, halogen, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy.

In some embodiments of compounds of Formula IIc, R⁴ and R⁶ are hydrogen,A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or —C(O)—,R¹⁵ is selected from the group consisting of hydrogen, halogen, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, and fluorosubstituted lower alkoxy, Z₂ is N or CR¹², Z₆ is N or CR¹⁶, R¹² and R¹⁶are independently selected from the group consisting of hydrogen,halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, andfluoro substituted lower alkoxy, and R⁵ is selected from the groupconsisting of hydrogen, halogen, lower alkyl, lower alkoxy, optionallysubstituted aryl, optionally substituted heteroaryl, and —NR²¹R²²,wherein R²¹ is hydrogen or lower alkyl, and R²² is hydrogen, loweralkyl, optionally substituted aryl or optionally substituted heteroaryl,and wherein the alkyl chain of R⁵, R²¹ or R²², when lower alkyl, or thealkyl chain of lower alkoxy is optionally substituted with one or moresubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino andcycloalkylamino, further wherein R³² is optionally substituted loweralkyl or —OR¹⁸, where R¹⁸ is as defined for Formula III.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIo:

all salts, prodrugs, tautomers and isomers thereof, wherein A, L₂, Z₂,Z₄, Z₅, Z₆, R⁴, R⁵, R⁶, and R³³ are as defined for Formula III.

In some embodiments of compounds of Formula IIIo, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, Z₂ is N or CR¹¹, Z₄ is N or CR¹⁴, Z₅ is N or CR¹⁵, Z₆ is N orCR¹⁶, and R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl and lower alkoxy,wherein the alkyl chain of lower alkyl or lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however,that any substitution on the alkyl carbon bound to the —O— of loweralkoxy is fluoro.

In some embodiments of compounds of Formula IIIo, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH— or—C(O)—, Z₂ is N or CR¹², Z₄ is N or CR¹⁴, Z₅ is N or CR¹⁵, Z₆ is N orCR¹⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower alkoxy, whereinthe alkyl chain of lower alkyl or lower alkoxy is optionally substitutedwith one or more substituents selected from the group consisting offluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino and cycloalkylamino, provided, however, that anysubstitution on the alkyl carbon bound to the —O— of lower alkoxy isfluoro, and R⁵ is selected from the group consisting of hydrogen,halogen, lower alkyl, lower alkoxy, optionally substituted aryl,optionally substituted heteroaryl, and NR²¹R²², wherein R²¹ is hydrogenor lower alkyl, and R²² is hydrogen, lower alkyl, optionally substitutedaryl or optionally substituted heteroaryl, and wherein the alkyl chainof R⁵, R²¹ or R²², when lower alkyl, or the alkyl chain of lower alkoxyis optionally substituted with one or more substituents selected fromthe group consisting of fluoro, —OH, —NH₂, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, fluoro substituted loweralkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino.

In some embodiments of compounds of Formula IIIo, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, Z₂ is N or CR¹², Z₄ is N or CR¹⁴, Z₅ is N or CR¹⁵, Z₆ is N orCR¹⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy, and R⁵ isselected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, optionally substituted aryl, optionally substitutedheteroaryl, and NR²¹R²², wherein R²¹ is hydrogen or lower alkyl, and R²²is hydrogen, lower alkyl, optionally substituted aryl or optionallysubstituted heteroaryl, and wherein the alkyl chain of R⁵, R²¹ or R²²,when lower alkyl, or the alkyl chain of lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIq:

all salts, prodrugs, tautomers, and isomers thereof,

-   -   wherein:    -   A₁ is —O—, —CR⁴⁰R⁴¹—, —C(O)— or —NR⁴⁸—;    -   Z₁₂ is N or CR⁵²;    -   Z₁₄ is N or CR⁵⁴;    -   Z₁₅ is N or CR⁵⁵;    -   Z₁₆ is N or CR⁵⁶;    -   R⁴⁰ and R⁴¹ are independently selected from the group consisting        of hydrogen, fluoro, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino; or    -   R⁴⁰ and R⁴¹ combine to form a 3-7 membered monocyclic cycloalkyl        or 5-7 membered monocyclic heterocycloalkyl, wherein the        monocyclic cycloalkyl or monocyclic heterocycloalkyl is        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   L₃ is selected from the group consisting of —NR⁴⁸—, —S—, —O—,        —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, —OCH(R⁴⁹)—, —C(O)NR⁴⁸—, —S(O)₂NR⁴⁸—,        —CH(R⁴⁹)NR⁴⁸—, —CH(R⁴⁹)O—, —CH(R⁴⁹)S—, —NR⁴⁸C(O)—, and        —NR⁴⁸S(O)₂—;    -   R⁵⁴ and R⁵⁵ are independently selected from the group consisting        of hydrogen, halogen, lower alkyl and lower alkoxy, wherein the        alkyl chain of lower alkyl or lower alkoxy is optionally        substituted with fluoro, —OH, —NH₂, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino or        cycloalkylamino, provided, however, that any substitution on the        alkyl carbon bound to the —O— of lower alkoxy is fluoro;    -   R⁵² and R⁵⁶ are independently selected from the group consisting        of hydrogen, halogen, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   R⁴⁹ is selected from the group consisting of hydrogen, lower        alkyl, and fluoro substituted lower alkyl;    -   Cy is selected from the group consisting of aryl, heteroaryl,        cycloalkyl, and heterocycloalkyl;    -   R³⁹ is selected from the group consisting of hydrogen, halogen,        lower alkyl, lower alkoxy, aryl, heteroaryl, and NR⁵⁰R⁵¹,        wherein the alkyl chain of lower alkyl or lower alkoxy is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino and        cycloalkylamino, and wherein aryl and heteroaryl are optionally        substituted with one or more independent substituents R²³;    -   R⁵⁰ is hydrogen or lower alkyl optionally substituted with one        or more substituents selected from the group consisting of        fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino and cycloalkylamino;    -   R⁵¹ is aryl or heteroaryl, wherein aryl and heteroaryl are        optionally substituted with one or more independent substituents        R²³;    -   R²³ at each occurrence is independently selected from the group        consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂,        —C(O)NH₂, —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —NR⁴⁸C(O)R⁵⁷, —NR⁴⁸S(O)₂R⁵⁷,        —S(O)₂R⁵⁷, —C(O)R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, —S(O)₂NR⁴⁸R⁵⁷,        halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl, wherein lower alkyl is optionally substituted with        one or more substituents selected from the group consisting of        fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R²³, or as substituents of lower alkyl, are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁵⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower        alkyl is optionally substituted with one or more substituents        selected from the group consisting of fluoro, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided,        however, that any substitution of the alkyl carbon bound to O,        S, or N of —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, or        —S(O)₂NR⁴⁸R⁵⁷ is fluoro, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁵⁷ or as substituents of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl carbon bound to O, S, or N of —OR⁵⁸, —SR⁵⁸,        —NR⁴⁸R⁵⁸—C(O)OR⁵, —C(O)NR⁴⁸R⁵⁸, or —S(O)₂NR⁴⁸R⁵⁸ is fluoro;    -   R⁴⁸ at each occurrence is independently hydrogen or lower alkyl;        and    -   t is 0, 1, 2, or 3.

In some embodiments of compounds of Formula IIIq, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—, more preferably —CH₂—. In someembodiments, A₁ is —CR⁴⁰R⁴¹— or —C(O)—, preferably —CH₂— or —C(O)—, morepreferably —CH₂—, and R⁵⁴ and R⁵⁵ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, and fluoro substituted lower alkoxy. In someembodiments, L₃ is —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, or —OCH(R⁴⁴)—, preferably—OCH(R⁴⁹)—. In some embodiments, A₁ is —CR⁴⁰R⁴¹— or —C(O)—, preferably—CH₂— or —C(O)—, more preferably —CH₂—, and L₃ is —NR⁴⁸CH(R⁴⁹)—,—SCH(R⁴⁹)—, or —OCH(R⁴⁹)—, preferably —OCH(R⁴⁹)—.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIId:

all salts, prodrugs, tautomers and isomers thereof, wherein A, Z₂, Z₅,Z₆, R⁴, R⁵, R⁶, R¹⁰, R¹¹ and R³³ are as defined for Formula III, and ris 0, 1, or 2.

In some embodiments of compounds of Formula IIId, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂ or—C(O)—, Z₂ is N or CR¹², Z₄ is N or CR¹⁴, Z; is N or CR¹⁵, Z₆ is N orCR¹⁶, and R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl and lower alkoxy,wherein the alkyl chain of lower alkyl or lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however,that any substitution on the alkyl carbon bound to the —O— of loweralkoxy is fluoro.

In some embodiments of compounds of Formula IIId, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, Z₂ is N or CR¹², Z₄ is N or CR⁴, Z₅ is N or CR¹⁵, Z₆ is N orCR¹⁶, R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower alkoxy, whereinthe alkyl chain of lower alkyl or lower alkoxy is optionally substitutedwith one or more substituents selected from the group consisting offluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino and cycloalkylamino, provided, however, that anysubstitution on the alkyl carbon bound to the —O— of lower alkoxy isfluoro, R¹⁰ and R¹¹ are independently selected from the group consistingof hydrogen, fluoro, lower alkyl, and fluoro substituted lower alkyl,and R⁵ is selected from the group consisting of hydrogen, halogen, loweralkyl, lower alkoxy, optionally substituted aryl, optionally substitutedheteroaryl, and NR²¹R²², wherein R²¹ is hydrogen or lower alkyl, and R²²is hydrogen, lower alkyl, optionally substituted aryl or optionallysubstituted heteroaryl, and wherein the alkyl chain of R⁵, R²¹ or R²²,when lower alkyl, or the alkyl chain of lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino.

In some embodiments of compounds of Formula IId, R⁴ and R⁶ are hydrogen,A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or —C(O)—,Z₂ is N or CR¹², Z₄ is N or CR¹⁴, Z₅ is N or CR¹⁵, Z₆ is N or CR¹⁶, R¹²,R¹⁴, R¹⁵ and R¹⁶ are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy, R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, fluoro,lower alkyl, and fluoro substituted lower alkyl, and R⁵ is selected fromthe group consisting of hydrogen, halogen, lower alkyl, lower alkoxy,optionally substituted aryl, optionally substituted heteroaryl, andNR²¹R²², wherein R²¹ is hydrogen or lower alkyl, and R²² is hydrogen,lower alkyl, optionally substituted aryl or optionally substitutedheteroaryl, and wherein the alkyl chain of R⁵, R²¹ or R²², when loweralkyl, or the alkyl chain of lower alkoxy is optionally substituted withone or more substituents selected from the group consisting of fluoro,—OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino and cycloalkylamino.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIe:

all salts, prodrugs, tautomers, and isomers thereof,

-   -   wherein:    -   A₁ is —O—, —CR⁴⁰R⁴¹—, —C(O)— or —NR⁴⁸—;    -   Z₂₂ is N or CR⁶²;    -   Z₂₄ is N or CR;    -   Z₂₅ is N or CR⁶⁵;    -   Z₂₆ is N or CR⁶⁶;    -   r is 0, 1, or 2;    -   R⁴⁰ and R⁴¹ are independently selected from the group consisting        of hydrogen, fluoro, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino; or    -   R⁴⁰ and R⁴¹ combine to form a 3-7 membered monocyclic cycloalkyl        or 5-7 membered monocyclic heterocycloalkyl, wherein the        monocyclic cycloalkyl or monocyclic heterocycloalkyl is        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   R⁶², R⁶⁴, R⁶⁵ and R⁶⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl and lower alkoxy,        wherein the alkyl chain of lower alkyl or lower alkoxy is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino and        cycloalkylamino, provided, however, that any substitution on the        alkyl carbon bound to the —O— of lower alkoxy is fluoro;    -   Cy is selected from the group consisting of aryl, heteroaryl,        cycloalkyl, and heterocycloalkyl;    -   R³⁹ is selected from the group consisting of hydrogen, halogen,        lower alkyl, lower alkoxy, aryl, heteroaryl, and NR⁵⁰R⁵¹,        wherein the alkyl chain of lower alkyl or lower alkoxy is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino and        cycloalkylamino, and wherein aryl and heteroaryl are optionally        substituted with one or more independent substituents R²³;    -   R⁵⁰ is hydrogen or lower alkyl optionally substituted with one        or more substituents selected from the group consisting of        fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino and cycloalkylamino;    -   R⁵¹ is aryl or heteroaryl, wherein aryl and heteroaryl are        optionally substituted with one or more independent substituents        R²³;    -   R¹³ at each occurrence is independently selected from the group        consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂,        —C(O)NH₂, —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —NR⁴⁸C(O)R⁵⁷, —NR⁴⁸S(O)₂R⁵⁷,        —S(O)₂R⁵⁷, —C(O)R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, —S(O)₂NR⁴⁸R⁵⁷,        halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl, wherein lower alkyl is optionally substituted with        one or more substituents selected from the group consisting of        fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R²³, or as substituents of lower alkyl, are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸,        —C(O)NR⁴⁸R⁵⁸—S(O)₂NR⁴⁸R⁸, halogen, lower alkyl, fluoro        substituted lower alkyl, and cycloalkylamino;    -   R⁵⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower        alkyl is optionally substituted with one or more substituents        selected from the group consisting of fluoro, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided,        however, that any substitution of the alkyl carbon bound to O,        S, or N of —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, or        —S(O)₂NR⁴⁸R⁵⁷ is fluoro, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁵⁷ or as substituents of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl carbon bound to O, S, or N of —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸,        —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸, or —S(O)₂NR⁴⁸R⁵⁸ is fluoro;    -   R⁴⁸ at each occurrence is independently hydrogen or lower alkyl;        and    -   t is 0, 1, 2, or 3.

In some embodiments of compounds of Formula IIIe, A, is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—. In some embodiments, A, is —CR⁴⁰R⁴¹—or —C(O)—, preferably —CH₂— or —C(O)—, and R⁶², R⁶⁴, R⁶⁵ and R⁶⁶ areindependently selected from the group consisting of hydrogen, halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluorosubstituted lower alkoxy.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIf:

all salts, prodrugs, tautomers and isomers thereof, wherein A, Z₂, Z₄,Z₅, Z₆, X, R⁴, R⁵, R⁶, R³⁴, R³⁵ and R⁸² are as defined for Formula III.

In some embodiments of compounds of Formula IIIf, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, Z₂ is N or CR¹², Z₄ is N or CR¹⁴, Z₅ is N or CR¹⁵, Z₆ is N orCR¹⁶, and R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl and lower alkoxy,wherein the alkyl chain of lower alkyl or lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however,that any substitution on the alkyl carbon bound to the —O— of loweralkoxy is fluoro.

In some embodiments of compounds of Formula IIIf, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, Z₂ is N or CR¹², Z₄ is N or CR¹⁴, Z₄ is N or CR¹⁵, is N or CR¹⁶,R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower alkoxy, whereinthe alkyl chain of lower alkyl or lower alkoxy is optionally substitutedwith one or more substituents selected from the group consisting offluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino and cycloalkylamino, provided, however, that anysubstitution on the alkyl carbon bound to the —O— of lower alkoxy isfluoro, and one of R³⁴ and R³⁵ is selected from the group consisting ofoptionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl andoptionally substituted heteroaryl, and the other of R³⁴ and R³⁵ ishydrogen or lower alkyl, or R³⁴ and R³⁵ together with the nitrogen towhich they are attached form optionally substituted 5-7 memberedheterocycloalkyl or optionally substituted 5 or 7 membered nitrogencontaining heteroaryl.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIg:

all salts, prodrugs, tautomers, and isomers thereof,

-   -   wherein:    -   A₁ is —O—, —CR⁴⁰R⁴¹—, —C(O)— or —NR⁴⁸—;    -   Z₃₂ is N or CR⁷²;    -   Z₃₄ is N or CR⁷⁴;    -   Z₃₅ is N or CR⁷⁵;    -   Z₃₆ is N or CR⁷⁶;    -   X is O or S;    -   R⁴⁸ each occurrence is independently hydrogen or lower alkyl;    -   R⁴⁰ and R⁴¹ are independently selected from the group consisting        of hydrogen, fluoro, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino; or    -   R⁴⁰ and R⁴¹ combine to form a 3-7 membered monocyclic cycloalkyl        or 5-7 membered monocyclic heterocycloalkyl, wherein the        monocyclic cycloalkyl or monocyclic heterocycloalkyl is        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   R⁷², R⁷⁴, R⁷⁵ and R⁷⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl and lower alkoxy,        wherein the alkyl chain of lower alkyl and lower alkoxy is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, —OH, —NH₂, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino and        cycloalkylamino, provided, however, that any substitution on the        alkyl carbon bound to the —O— of lower alkoxy is fluoro;    -   R⁶⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted lower        alkenyl, optionally substituted lower alkynyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —OH, —NH₂, —CN, —NO, —C(O)OH, —S(O)NH₂, —C(O)NH₂, —C(S)NH₂,        —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸,        —C(O)R⁶⁸, —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸,        —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸,        —NR⁶⁹C(O)NH₂, —NR⁶⁸C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸,        —NR⁶⁹S(O)₂NH₂, —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, and —S(O)₂R⁶⁸;    -   one of R⁶⁰ and R⁶¹ is lower alkyl, fluoro substituted lower        alkyl, or —(CH₂)₀₋₂R⁷⁰, and the other of R⁶⁰ and R⁶¹ is hydrogen        or lower alkyl;    -   or R⁶⁰ and R⁶¹ together with the nitrogen to which they are        attached form optionally substituted 5-7 membered        heterocycloalkyl or optionally substituted 5 or 7 membered        nitrogen containing heteroaryl;    -   R⁶⁸ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted lower alkenyl,        provided, however, that when R⁶⁸ is optionally substituted lower        alkenyl, no alkene carbon thereof is bound to N, S, O, S(O),        S(O)₂, C(O) or C(S) of —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸,        —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁸R⁶⁸, —C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸,        —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸, —NR⁶⁹C(O)NH₂,        —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸, —NR⁶⁹S(O)₂NH₂,        —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or —S(O)₂R⁶⁸, optionally        substituted lower alkynyl, provided, however, that when R⁶⁸ is        optionally substituted lower alkynyl, no alkyne carbon thereof        is bound to N, S, O, S(O), S(O)₂, C(O) or C(S) of —OR⁶⁸, —SR⁶⁸,        —NR⁶⁹R⁶⁸, —C(O)R⁶⁸, —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸,        C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸,        —NR⁶⁹S(O)₂R⁶⁸, —NR⁶⁹C(O)NH₂, —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂,        —NR⁶⁹C(S)NR⁶⁹R⁶⁸, —NR⁶⁹S(O)₂NH₂, —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or        —S(O)₂R⁶⁸, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl, and        optionally substituted heteroaryl;    -   R⁶⁹ is hydrogen or optionally substituted lower alkyl;    -   R⁷⁰ is selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R⁸² is hydrogen or lower alkyl.

In some embodiments of compounds of Formula IIIg, A, is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIg, A, is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—, and R⁶⁷ is selected from the groupconsisting of hydrogen, halogen, optionally substituted lower alkyl,optionally substituted lower alkenyl, optionally substituted loweralkynyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —CN, —S(O)₂NH₂, —C(O)NH₂, —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸,—C(S)R⁶⁸, —C(O)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸,—S(O)R⁶⁸, and —S(O)₂R⁶⁸.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIh:

all salts, prodrugs, tautomers and isomers thereof, wherein A, X, R⁴,R⁵, R⁶, R³⁷, R³⁸, R⁴², R⁴³, R⁴⁵R⁴⁶, and R⁴⁷ are as defined for FormulaIII.

In some embodiments of compounds of Formula IIIh, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, and R⁴², R⁴³, R⁴⁵, R⁴⁶ and R⁴⁷ are independently selected fromthe group consisting of hydrogen, halogen, —OH, —CN, —NO₂, —NH₂, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substitutedlower alkoxy, lower alkylthio, fluoro substituted lower alkyl,mono-alkylamino, di-alkylamino, and cycloalkylamino, further wherein atleast one of, at least two of, at least three of, at least four of, orpreferably all of R⁴², R⁴³, R⁴⁵, R⁴⁶ and R⁴⁷ are hydrogen.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIi:

all salts, prodrugs, tautomers, and isomers thereof,

-   -   wherein:    -   A₁ is —O—, —CR⁴⁰R⁴¹—, —C(O)— or —NR⁴⁸—;    -   X is O or S;    -   R⁴⁸ at each occurrence is independently hydrogen or lower alkyl;    -   R⁴⁰ and R⁴¹ are independently selected from the group consisting        of hydrogen, fluoro, lower alkyl, fluoro substituted lower        alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, and cycloalkylamino; or    -   R⁴⁰ and R⁴¹ combine to form a 3-7 membered monocyclic cycloalkyl        or 5-7 membered monocyclic heterocycloalkyl, wherein the        monocyclic cycloalkyl or monocyclic heterocycloalkyl is        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   R⁶⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted lower        alkenyl, optionally substituted lower alkynyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂, —C(O)NH₂, —C(S)NH₂,        —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸,        —C(O)R⁶⁸, —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸,        —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸,        —NR⁶⁹C(O)NH₂, —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸,        —NR⁶⁹S(O)₂NH₂, —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, and —S(O)₂R⁶⁸;    -   one of R⁶⁰ and R⁶¹ is lower alkyl, fluoro substituted lower        alkyl, or —(CH₂)₀₋₂R⁷⁰ and the other of R⁶⁰ and R⁶¹ is hydrogen        or lower alkyl;    -   or R⁶⁰ and R⁶¹ together with the nitrogen to which they are        attached form optionally substituted 5-7 membered        heterocycloalkyl or optionally substituted 5 or 7 membered        nitrogen containing heteroaryl;    -   R⁶⁸ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted lower alkenyl,        provided, however, that when R⁶⁸ is optionally substituted lower        alkenyl, no alkene carbon thereof is bound to N, S, O, S(O),        S(O)₂, C(O) or C(S) of —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸,        —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸,        —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶⁸S(O)₂R⁶⁸, —NR⁶⁹C(O)NH₂,        —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸,        —NR⁶⁹S(O)₂NH₂—NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or —S(O)₂R⁶⁸,        optionally substituted lower alkynyl, provided, however, that        when R⁶⁸ is optionally substituted lower alkynyl, no alkyne        carbon thereof is bound to N, S, O, S(O), S(O)₂, C(O) or C(S) of        —OR⁶⁸, —SR¹⁶, —NR⁶⁹R⁶⁸, —C(O)R⁸, —C(S)R⁶⁵, —C(O)OR⁶⁸,        —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸,        —NR⁶⁹C(S)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸, —NR⁶⁹C(O)NH₂, —NR⁶⁹C(O)NR⁶⁹R⁶⁸,        —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸, —NR⁶⁹S(O)₂NH₂,        —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or —S(O)₂R⁶⁸, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R⁶⁹ is hydrogen or optionally substituted lower alkyl; and    -   R⁷⁰ is selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl.

In some embodiments of compounds of Formula IIIi, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—.

In some embodiments of compounds of Formula IIIi, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—, and R^(b)7 is selected from thegroup consisting of hydrogen, halogen, optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substitutedlower alkynyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —CN, —S(O)₂NH₂, —C(O)NH₂, —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸,—C(S)R⁶⁸, —C(O)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁸C(O)R⁶⁹, —NR⁶⁹S(O)₂R⁶⁸,—S(O)R⁶⁸, and —S(O)₂R⁶⁸.

In some embodiments of compounds of Formula IIIi, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—, more preferably —C(O)—, R⁶⁷ isselected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, optionally substituted aryl, optionally substitutedheteroaryl, and NR²¹R²², wherein R²¹ is hydrogen or lower alkyl, and R²²is hydrogen, lower alkyl, optionally substituted aryl or optionallysubstituted heteroaryl, and wherein the alkyl chain of R⁶⁷, R²¹ or R²²,when lower alkyl, or the alkyl chain of lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, and one of R⁶⁰ andR⁶¹ is lower alkyl or fluoro substituted lower alkyl, and the other ofR⁶⁰ and R⁶¹ is hydrogen or lower alkyl. In some embodiments, A₁ is—C(O)—, R⁶⁷ is optionally substituted aryl or optionally substitutedheteroaryl, and one of R⁶⁰ and R⁶¹ is lower alkyl or fluoro substitutedlower alkyl, and the other of R⁶⁰ and R⁶¹ is hydrogen or lower alkyl.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIj:

all salts, prodrugs, tautomers and isomers thereof, wherein A, R⁴, R⁵,R⁶, R¹², R¹⁴, R¹⁵, R¹⁶, and R³⁶ are as defined for Formula III.

In some embodiments of compounds of Formula IIIj, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, and R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl and lower alkoxy,wherein the alkyl chain of lower alkyl or lower alkoxy is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however,that any substitution on the alkyl carbon bound to the —O— of loweralkoxy is fluoro, preferably wherein R¹⁴ and R¹⁵ are hydrogen, morepreferably wherein R¹² is fluoro, R¹⁶ is hydrogen, fluoro or chloro, andR¹⁴ and R¹⁵ are hydrogen.

In some embodiments of compounds of Formula IIIj, R⁴ and R⁶ arehydrogen, A is —O—, —CR^(a)R^(b)—, —NR¹—, or —C(O)—, preferably —CH₂— or—C(O)—, R¹², R¹⁴, R¹⁵ and R¹⁶ are independently selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower alkoxy, whereinthe alkyl chain of lower alkyl or lower alkoxy is optionally substitutedwith one or more substituents selected from the group consisting offluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino and cycloalkylamino, provided, however, that anysubstitution on the alkyl carbon bound to the —O— of lower alkoxy isfluoro, preferably wherein R¹⁴ and R¹⁵ are hydrogen, more preferablywherein R¹² is fluoro, R¹⁶ is hydrogen, fluoro or chloro, and R¹⁴ andR¹⁵ are hydrogen, and R³⁶ is selected from the group consisting ofoptionally substituted C₂₋₆ alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, and —NR¹⁹R²⁰, where R¹⁹ and R²⁰ areas defined for Formula III, further wherein one of R¹⁹ and R²⁰ ishydrogen or optionally substituted lower alkyl, and the other of R¹⁹ andR²⁰ is selected from the group consisting of hydrogen, optionallysubstituted lower alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl and optionallysubstituted heteroaryl.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIIk:

all salts, prodrugs, tautomers and isomers thereof,

-   -   wherein:    -   A₁ is —O—, —CR⁴⁰R⁴¹—, —C(O)— or —NR⁴⁸—;    -   R⁸¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted lower        alkenyl, optionally substituted lower alkynyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂, —C(O)NH₂, —C(S)NH₂,        —NHC(O)N₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸,        —C(O)R⁶⁸, —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸,        —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶S(O)₂R⁶,        —NR⁶⁹C(O)NH₂, —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸,        —NR⁶⁹S(O)₂NH₂, —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, and —S(O)₂R⁶⁸;    -   R⁷¹ and R⁷⁸ are independently selected from the group consisting        of hydrogen, halogen, C₁₋₃ alkyl, and fluoro substituted C₁₋₃        alkyl;    -   R⁷⁷ is selected from the group consisting of substituted methyl,        optionally substituted C₂₋₆ alkyl, optionally substituted aryl,        optionally substituted heteroaryl, and —NR⁷⁹R⁸⁰, wherein methyl        is substituted with one or more substituents selected from the        group consisting of optionally substituted aryl and optionally        substituted heteroaryl;    -   R⁶⁸ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted lower alkenyl,        provided, however, that when R⁶⁸ is optionally substituted lower        alkenyl, no alkene carbon thereof is bound to N, S, O, S(O),        S(O)₂, C(O) or C(S) of —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸,        —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸,        —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶S(O)₂R⁶, —NR⁶⁹C(O)NH₂,        —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸, —NR⁶⁹S(O)₂NH₂,        —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or —S(O)₂R⁶⁸, optionally        substituted lower alkynyl, provided, however, that when R⁶⁸ is        optionally substituted lower alkynyl, no alkyne carbon thereof        is bound to N, S, O, S(O), S(O)₂, C(O) or C(S) of —OR⁶⁸, —SR⁶⁸,        —NR⁶⁹R⁶⁸, —C(O)R⁶⁸, —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸,        —C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸,        —NR⁶⁹S(O)₂R⁶⁸, —NR⁶⁹C(O)NH₂, —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂,        —NR⁶⁹C(S)NR⁶⁹R⁶⁸, —NR⁶⁹S(O)₂NH₂, —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or        —S(O)₂R⁶⁸, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl, and        optionally substituted heteroaryl;    -   R⁶⁹ is hydrogen or optionally substituted lower alkyl; and    -   R⁷⁹ and R⁸⁰ are independently hydrogen or optionally substituted        lower alkyl, or R⁷⁹ and R⁸⁰ combine with the nitrogen to which        they are attached to form optionally substituted 5-7 membered        heterocycloalkyl.

In some embodiments of compounds of Formula IIIk, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—, more preferably —C(O)—.

In some embodiments of compounds of Formula IIIk, A₁ is —CR⁴⁰R⁴¹— or—C(O)—, preferably —CH₂— or —C(O)—, more preferably —C(O)—, and R⁸¹ isselected from the group consisting of hydrogen, halogen, optionallysubstituted lower alkyl, optionally substituted lower alkenyl,optionally substituted lower alkynyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, —CN, —S(O)₂NH₂, —C(O)NH—, —OR⁶⁸,—SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸, —C(S)R⁶⁸, —C(O)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸,—NR⁶⁹C(O)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸, —S(O)R⁶⁸, and —S(O)₂R⁶⁸.

In some embodiments, compounds of Formula III have the structureaccording to the following sub-generic structure Formula IIm:

all salts, prodrugs, tautomers and isomers thereof,

-   -   wherein:    -   R⁸¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted lower        alkenyl, optionally substituted lower alkynyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂, —C(O)NH₂, —C(S)NH₂,        —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —OR⁶, —SR⁶⁸, —NR⁶⁹R⁶⁸,        —C(O)R⁶⁸, —C(S)R⁶⁹, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸,        —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶⁹S(O)₂R⁶,        —NR⁶⁸C(O)NH₂, —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸,        —NR⁶⁹S(O)₂NH₂, —NR⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, and —S(O)₂R⁶⁸;    -   R⁸³ is selected from the group consisting of hydrogen, fluoro        and chloro;    -   R¹¹² is selected from the group consisting of optionally        substituted C₂₋₆ alkyl, optionally substituted aryl, optionally        substituted heteroaryl, and —NR⁷⁹R⁸⁰;    -   R⁶⁸ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted lower alkenyl,        provided, however, that when R⁶⁸ is optionally substituted lower        alkenyl, no alkene carbon thereof is bound to N, S, O, S(O),        S(O)₂, C(O) or C(S) of —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸,        —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸, —C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸,        —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸, —NR⁶⁹C(O)NH₂,        —NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂, —NR⁶⁹C(S)NR⁶⁹R⁶⁸, —NR⁶⁹S(O)₂NH₂,        —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or —S(O)₂R⁶⁸, optionally        substituted lower alkynyl, provided, however, that when R⁶⁸ is        optionally substituted lower alkynyl, no alkyne carbon thereof        is bound to N, S, O, S(O), S(O)₂, C(O) or C(S) of —OR⁶⁸, —SR⁶⁸,        —NR⁶⁹R⁶⁸, —C(O)R⁶⁹, —C(S)R⁶⁸, —C(O)OR⁶⁸, —C(O)NR⁶⁹R⁶⁸,        —C(S)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹C(S)R⁶⁸,        —NR⁶⁹S(O)₂R⁶⁸, —NR⁶⁹C(O)NH₂—NR⁶⁹C(O)NR⁶⁹R⁶⁸, —NR⁶⁹C(S)NH₂,        —NR⁶⁹C(S)NR⁶⁹R⁶⁸, —NR⁶⁹S(O)₂NH₂, —NR⁶⁹S(O)₂NR⁶⁹R⁶⁸, —S(O)R⁶⁸, or        —S(O)₂R⁶⁸, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl, and        optionally substituted heteroaryl;    -   R⁶⁹ is selected from the group consisting of hydrogen and        optionally substituted lower alkyl; and    -   R⁷⁹ and R⁸⁰ are independently hydrogen or optionally substituted        lower alkyl, or R⁷⁹ and R⁸⁰ combine with the nitrogen to which        they are attached to form optionally substituted 5-7 membered        heterocycloalkyl.

In some embodiments of compounds of Formula IIIm, R⁸¹ is selected fromthe group consisting of hydrogen, halogen, optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substitutedlower alkynyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —CN, —S(O)₂NH₂, —C(O)NH₂, —OR⁶⁸, —SR⁶⁸, —NR⁶⁹R⁶⁸, —C(O)R⁶⁸,—C(S)R⁶⁸, —C(O)NR⁶⁹R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁶⁹C(O)R⁶⁸, —NR⁶⁹S(O)₂R⁶⁸,—S(O)R⁶⁸, and —S(O)₂R⁶⁸.

The compounds of Formulae IIIa-IIIq, and all sub-embodiments detailedherein, may be used to treat a subject suffering from or at risk for anyof the protein kinase mediated diseases or conditions contemplatedherein.

In one aspect, the present invention includes compounds that are usefulas intermediates in the preparation of compounds of Formula III, thecompounds having a structure selected from the group consisting ofFormula IV, Formula V, Formula VI, Formula VII, Formula VIII, andFormula IX as follows:

-   -   wherein:    -   Z₂, Z₄, Z₅, Z₆, L₂, X, s, R¹⁵, R³¹, R³², R³³, R³⁷, R³⁸, R⁴²,        R⁴³, R⁴⁵, R⁴⁶, and R⁴⁷ are as defined for Formula III;    -   R¹⁰⁸ is selected from the group consisting of —C(O)R¹⁴, —CH₂I,        —CH₂Cl, —CH₂Br, —CH₂OH, and —CH₂OS(O)₂R¹⁰⁹;    -   R¹⁰⁹ is selected from the group consisting of lower alkyl and        aryl;    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl;    -   R⁸⁵ is selected from the group consisting of hydrogen, a        nitrogen protecting group, —S(O)₂R⁸⁷, —C(O)NR⁸⁸SR⁸⁹, and        —C(S)NR⁸⁸R⁸⁹;    -   R⁸⁶ is selected from the group consisting of hydrogen, lower        alkyl, and a nitrogen protecting group;    -   R⁸⁷ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted lower alkenyl,        provided, however, that when R⁸⁷ is optionally substituted lower        alkenyl, no alkene carbon thereof is bound to S(O)₂, optionally        substituted lower alkynyl, provided, however, that when R⁸⁷ is        optionally substituted lower alkynyl, no alkyne carbon thereof        is bound to S(O)₂, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl, and —NR⁹⁰R⁹¹; and    -   R⁸⁸, R⁸⁹, R⁹⁰ and R⁹¹ are independently selected from the group        consisting of hydrogen, optionally substituted lower alkyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl and optionally        substituted heteroaryl; or    -   R⁸⁸ and R⁸⁹ together with the nitrogen to which they are        attached form optionally substituted 5-7 membered        heterocycloalkyl or optionally substituted 5 or 7 membered        nitrogen containing heteroaryl.

In some embodiments of compounds of Formulae IV, V, VI, VII, or VII,R¹⁰⁸ is —C(O)R⁸⁴, preferably wherein R⁸⁴ is hydrogen. In someembodiments of compounds of Formulae IV, V, VI, VII, or VIII, Z₂ is N orCR¹², Z₄ is N or CR¹⁴, Z₅ is N or CR⁵, and Z₆ is N or CR¹⁶ and R¹², R¹⁴,R¹⁵, R¹⁶, R¹⁷, R⁴², R⁴³, R⁴⁵, R⁴⁶ and R⁴⁷ are independently selectedfrom the group consisting of hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, and fluoro substituted loweralkoxy.

In some embodiments, compounds of Formula IV have the structureaccording to the following sub-generic structure Formula IVa:

-   -   wherein:    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl;    -   R⁹², R⁹³, R⁹⁵, and R⁹⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl, fluoro substituted        lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   L₄ is selected from the group consisting of —NR⁴⁸—, —S—, —O—,        —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, —OCH(R⁴⁹)—, —C(O)NR⁴⁸—, —S(O)₂NR⁴⁸—,        —CH(R⁴⁹)NR⁴⁸—, —CH(R⁴⁹)O—, —CH(R⁴⁹)S—, —NR⁴⁸C(O)—, and        —NR¹⁴S(O)₂—;    -   Cy is selected from the group consisting of cycloalkyl,        heterocycloalkyl, aryl and heteroaryl;    -   R⁹⁷ at each occurrence is independently selected from the group        consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂,        —C(O)NH₂, —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —NR⁴⁸C(O)R⁵⁷, —NR⁴⁸S(O)₂R⁵⁸,        —S(O)₂R⁵⁷, —C(O)R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, —S(O)₂NR⁴⁸R⁵⁷,        halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl, wherein lower alkyl is optionally substituted with        one or more substituents selected from the group consisting of        fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁹⁷, or as substituents of lower alkyl, are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁴⁹ is selected from the group consisting of hydrogen, lower        alkyl, and fluoro substituted lower alkyl;    -   R⁵⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower        alkyl is optionally substituted with one or more substituents        selected from the group consisting of fluoro, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided,        however, that any substitution of the alkyl carbon bound to O,        S, or N of —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, or        —S(O)₂NR⁴⁸R⁵⁷ is fluoro, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁵⁷ or as substituents of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino; and    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl carbon bound to O, S, or N of —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸,        —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸, or —S(O)₂NR⁴⁸R⁵⁸ is fluoro;    -   R⁴⁸ at each occurrence is independently hydrogen or lower alkyl;        and    -   u is 0, 1, 2, or 3.

In one embodiment of compounds of Formula IVa, at least two of R⁹², R⁹³,R⁹⁵ and R⁹⁶ are hydrogen. In one embodiment, at least two of R⁹², R⁹³,R⁹⁵ and R⁹⁶ are hydrogen, L₄ is —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, or—OCH(R⁴⁹)—, preferably L₄ is —OCH₂—, Cy is aryl or heteroaryl, and eachR⁹⁷ is independently selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluorosubstituted lower alkoxy.

In some embodiments, compounds of Formula IV have the structureaccording to the following sub-generic structure Formula IVb:

wherein R⁸⁴, R⁹², R⁹³, R⁹⁵, R⁹⁶, R⁹⁷, Cy and u are as defined forFormula IVa and r is 0, 1 or 2.

In some embodiments of compounds of Formula IVb, at least two of R⁹²,R⁹³, R⁹⁵ and R⁹⁶ are hydrogen. In some embodiments, at least two of R⁹²,R⁹³, R⁹⁵ and R⁹⁶ are hydrogen, Cy is aryl or heteroaryl, and each R⁹⁷ isindependently selected from the group consisting of halogen, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, and fluorosubstituted lower alkoxy.

In some embodiments, compounds of Formula V have the structure accordingto the following sub-generic structure Formula Va:

-   -   wherein:    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl;    -   R⁹², R⁹³, R⁹⁵, and R⁹⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl, fluoro substituted        lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   R⁹⁸ is selected from the group consisting of hydrogen, lower        alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro        substituted lower alkoxy; and    -   s is 0, 1, or 2;

In some embodiments, compounds of Formula VI have the structureaccording to the following sub-generic structure Formula VIa:

-   -   wherein:    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl:    -   R⁹², R⁹⁴, R⁹⁵, and R⁹⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl, fluoro substituted        lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   L₄ is selected from the group consisting of —NR¹⁴—, —S—, —O—,        —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, —OCH(R⁴⁹)—, —C(O)NR⁴⁸—, —S(O)₂NR⁴⁸—,        —CH(R⁴⁹)NR⁴⁸—, —CH(R⁴⁹)O—, —CH(R⁴⁹)S—, —NR⁴⁸OC(O)—, and        —NR⁴⁸S(O)₂—;    -   Cy is selected from the group consisting of cycloalkyl,        heterocycloalkyl, aryl and heteroaryl;    -   R⁹⁷ at each occurrence is independently selected from the group        consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH, —S(O)₂NH₂,        —C(O)NH₂, —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —NR⁴⁸C(O)R⁵⁷, —NR⁴⁸S(O)₂R⁵,        —S(O)₂R⁵⁷, —C(O)R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, —S(O)₂NR⁴⁸R⁵⁷,        halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl, wherein lower alkyl is optionally substituted with        one or more substituents selected from the group consisting of        fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower        alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,        di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁹⁷, or as substituents of lower alkyl, are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)₂R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁴⁹ is selected from the group consisting of hydrogen, lower        alkyl, and fluoro substituted lower alkyl;    -   R⁵⁷ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower        alkyl is optionally substituted with one or more substituents        selected from the group consisting of fluoro, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, provided,        however, that any substitution of the alkyl carbon bound to O,        S, or N of —OR⁵⁷, —SR⁵⁷, —NR⁴⁸R⁵⁷, —C(O)OR⁵⁷, —C(O)NR⁴⁸R⁵⁷, or        —S(O)₂NR⁴⁸R⁵⁷ is fluoro, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl as R⁵⁷ or as substituents of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —C(O)OH,        —S(O)₂NH₂, —C(O)NH₂, —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸, —NR⁴⁸C(O)R⁵⁸,        —NR⁴⁸S(O)R⁵⁸, —S(O)₂R⁵⁸, —C(O)R⁵⁸, —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸,        —S(O)₂NR⁴⁸R⁵⁸, halogen, lower alkyl, fluoro substituted lower        alkyl, and cycloalkylamino;    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, provided, however, that any substitution of the        alkyl carbon bound to O, S, or N of —OR⁵⁸, —SR⁵⁸, —NR⁴⁸R⁵⁸,        —C(O)OR⁵⁸, —C(O)NR⁴⁸R⁵⁸, or —S(O)₂NR⁴⁸R⁵⁸ is fluoro;    -   R⁴⁸ at each occurrence is independently hydrogen or lower alkyl;        and    -   u is 0, 1, 2 or 3.

In some embodiments of compounds of Formula VIa, at least two of R⁹²,R⁹⁴, R⁹⁵ and R¹⁶ are hydrogen. In some embodiments, at least two of R⁹²,R⁹⁴, R⁹⁵ and R⁹⁶ are hydrogen, L₄ is —NR⁴⁸CH(R⁴⁹)—, —SCH(R⁴⁹)—, or—OCH(R⁴⁹)—, preferably L₄ is —OCH₂—, Cy is aryl or heteroaryl, and eachR⁹⁷ is independently selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluorosubstituted lower alkoxy.

In some embodiments, compounds of Formula VI have the structureaccording to the following sub-generic structure Formula VIb:

-   -   wherein R⁴⁴, R⁹², R⁹⁴, R⁹⁵, R⁹⁶, R⁹⁷, Cy and u are as defined        for Formula VIa and r is 0, 1 or 2.

In some embodiments of compounds of Formula VIb, at least two of R⁹²,R⁹⁴, R⁹⁵ and R⁹⁶ are hydrogen. In some embodiments, at least two of R⁹²,R⁹⁴, R⁹⁵ and R⁹⁶ are hydrogen, Cy is aryl or heteroaryl, and each R⁹⁷ isindependently selected from the group consisting of halogen, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, and fluorosubstituted lower alkoxy.

In some embodiments, compounds of Formula VII have the structureaccording to the following sub-generic structure Formula VIIa:

-   -   wherein:    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl;    -   R⁹², R⁹⁴, R⁹⁵, and R⁹⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl, fluoro substituted        lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   R⁹⁹ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted aryl, optionally        substituted heteroaryl, and —NR⁷⁹R⁸⁰; and    -   R⁷⁹ and R⁸⁰ are independently hydrogen or optionally substituted        lower alkyl, or R⁷⁹ and R⁸⁰ combine with the nitrogen to which        they are attached to form a optionally substituted 5-7 membered        heterocycloalkyl.

In some embodiments of compounds of Formula VIIa, one of R⁹² and R⁹⁶ isselected from the group consisting of hydrogen, halogen, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, and fluoro substitutedlower alkoxy, and the other of R⁹² and R⁹⁶ is selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,lower alkoxy, and fluoro substituted lower alkoxy; in furtherembodiments, one of R⁹² and R⁹⁶ is hydrogen, fluoro or chloro, and theother of R⁹² and R⁹⁶ is fluoro or chloro; in further embodiments, R⁹² isfluoro and R⁹⁶ is hydrogen, fluoro, or chloro; in further embodiments,R⁹² and R⁹⁶ are both fluoro.

In some embodiments of compounds of Formula VIIa, R⁹⁴ and R⁹⁵ arehydrogen; in further embodiments, one of R⁹² and R⁹⁶ is selected fromthe group consisting of hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, and fluoro substituted loweralkoxy and the other of R⁹² and R⁹⁶ is selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,lower alkoxy, and fluoro substituted lower alkoxy; in furtherembodiments, one of R⁹² and R⁹⁶ is selected from hydrogen, fluoro orchloro and the other of R⁹² and R⁹⁶ is selected from fluoro or chloro;in further embodiments, R⁹² is fluoro and R⁹⁶ is selected from hydrogen,fluoro, or chloro; in further embodiments, R⁹² and R⁹⁶ are both fluoro.

In some embodiments, compounds of Formula VII have the structureaccording to the following sub-generic structure Formula VIIb:

-   -   wherein:    -   X is O or S;    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl;    -   R⁹², R⁹⁴, R⁹⁵, and R⁹⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl, fluoro substituted        lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   R⁸² is hydrogen or lower alkyl;    -   one of R¹⁰⁰ and R¹⁰¹ is lower alkyl, fluoro substituted lower        alkyl, or —(CH₂)₀₋₂R⁷⁰), and the other of R¹⁰⁰ and R¹⁰¹ is        hydrogen or lower alkyl; or    -   R¹⁰⁰ and R¹⁰¹ together with the nitrogen to which they are        attached form optionally substituted 5-7 membered        heterocycloalkyl or optionally substituted 5 or 7 membered        nitrogen containing heteroaryl; and    -   R⁷⁰ is selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl.

In some embodiments of compounds of Formula VIIb, at least two of R⁹²,R⁹⁴, R⁹⁵ and R⁹⁶ are hydrogen. In some embodiments, at least two of R⁹²,R⁹⁴, R⁹⁵ and R⁹⁶ are hydrogen, and R⁷⁰ is aryl or heteroaryl, whereinaryl and heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, and fluoro substitutedlower alkoxy.

In some embodiments, compounds of Formula VIII have the structureaccording to the following sub-generic structure Formula VIIIa:

-   -   wherein:    -   X is O or S;    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl;    -   R¹⁰², R¹⁰³, R¹⁰⁵, R¹⁰⁶, and R¹⁰⁷ are independently selected from        the group consisting of hydrogen, halogen, lower alkyl, fluoro        substituted lower alkyl, lower alkoxy, and fluoro substituted        lower alkoxy;    -   one of R¹⁰⁰ and R¹⁰¹ is lower alkyl, fluoro substituted lower        alkyl, or —(CH₂)₀₋₂R⁷⁰ and the other of R¹⁰⁰ and R¹⁰¹ is        hydrogen or lower alkyl;    -   or R¹⁰⁰ and R¹⁰¹ together with the nitrogen to which they are        attached form optionally substituted 5-7 membered        heterocycloalkyl or optionally substituted 5 or 7 membered        nitrogen containing heteroaryl; and    -   R⁷⁰ is selected from the group consisting of optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl.

In some embodiments of compounds of Formula VIIIa, at least two, also atleast three, also at least four, or all of R¹⁰², R¹⁰³, R¹⁰⁵, R¹⁰⁰, andR¹⁰⁷ are hydrogen. In some embodiments, at least two, also at leastthree, also at least four, or all of R¹⁰², R¹⁰³, R¹⁰⁵, R¹⁰⁶, and R¹⁰⁷are hydrogen, and R⁷⁰ is aryl or heteroaryl, wherein aryl and heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy.

In some embodiments, compounds of Formula IX have the structureaccording to the following sub-generic structure Formula IXa:

-   -   wherein:    -   R⁸⁴ is selected from the group consisting of hydrogen, lower        alkoxy, —OH, and —Cl;    -   R⁹², R⁹⁵, and R⁹⁶ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl, fluoro substituted        lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;    -   R⁹⁸ is selected from the group consisting of hydrogen, lower        alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro        substituted lower alkoxy; and    -   s is 0, 1, or 2;

In some embodiments of any of the above embodiments of compounds ofFormula IVa, IVb, Va, VIIa, VIIb, VIIa, VIIb, VIIIa, or IXa, R⁸⁴ ishydrogen.

In some embodiments of the above compounds, compounds are excluded whereN (except where N is a heteroaryl ring atom), O, or S is bound to acarbon that is also bound to N (except where N is a heteroaryl ringatom), O, or S; or where N (except where N is a heteroaryl ring atom),O, C(S), C(O), or S(O), (n is 0-2) is bound to an alkene carbon of analkenyl group or bound to an alkyne carbon of an alkynyl group;accordingly, in some embodiments compounds which include linkages suchas the following are excluded from the present invention: —NR—CH₂—NR—,—O—CH₂—NR—, —S—CH₂—NR—, —NR—CH₂—O—, —O—CH₂—O—, —S—CH₂—O—, —NR—CH₂—S—,—O—CH₂—S—, —S—CH₂—S—, —NR—CH═CH—, —CH═CH—NR—, —NR—C≡C—, —C≡C—NR—,—O—CH═CH—O, —CH═CH—O—, —O—C≡C—, —C≡C—O—, —S(O)₀₋₂—CH═CH—,—CH═CH—S(O)₀₋₂—, —S(O)₀₋₂—C≡C—, —C≡C—S(O)₀₋₂—, —C(O)—CH═CH—,—CH═CH—C(O)—, —C≡C—C(O)—, or —C(O)—C≡C—, —C(S)—CH═CH—, —CH═CH—C(S)—,—C≡C—C(S)—, or —C(S)—C≡C—.

In reference to compounds herein, specification of a compound or groupof compounds includes pharmaceutically acceptable salts of suchcompound(s) unless clearly indicated to the contrary, prodrug(s), andall stereoisomers. In reference to compositions, kits, methods of use,etc. of compounds of Formula I described herein, it is understood that acompound of Formula I includes compounds of Formulae Ia-Iz, and allsub-embodiments thereof, compounds of Formula II, including FormulaeIIa-IIo, and all sub-embodiments thereof, and compounds of Formula III,including Formulae IIIa-IIIq, and all sub-embodiments thereof, unlessindicated otherwise. In reference to compositions, kits, methods of use,etc. of compounds of Formula II described herein, it is understood thatthis includes compounds of Formulae IIa-IIo, and all sub-embodimentsthereof, unless indicated otherwise. In reference to compositions, kits,methods of use, etc. of compounds of Formula III described herein, it isunderstood that this includes compounds of Formulae IIIa-IIIq, and allsub-embodiments thereof, unless indicated otherwise.

In one aspect, the invention provides methods for treating a proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of Formula I. The terms “treat,” “therapy,” and like termsrefer to the administration of material, e.g., compound of Formula I, inan amount effective to prevent, alleviate, or ameliorate one or moresymptoms of a disease or condition, i.e., indication, and/or to prolongthe survival of the subject being treated. The term “protein kinasemediated disease or condition” refers to a disease or condition in whichthe biological function of a protein kinase affects the developmentand/or course of the disease or condition, and/or in which modulation ofthe protein kinase alters the development, course, and/or symptoms ofthe disease or condition. A protein kinase mediated disease or conditionincludes a disease or condition for which modulation provides atherapeutic benefit, e.g. wherein treatment with protein kinaseinhibitors, including compounds described herein, provides a therapeuticbenefit to the subject suffering from or at risk of the disease orcondition. In one aspect, the method involves administering to thesubject an effective amount of a compound of Formula I in combinationwith one or more other therapies for the disease or condition.

In one aspect, the invention provides methods for treating a proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of any one or more of Formula Ia through Formula Iz, and allsub-embodiments thereof.

In another aspect, the invention provides methods for treating a proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of Formula II.

In another aspect, the invention provides methods for treating a proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of any one or more of Formula IIa through Formula IIo, and allsub-embodiments thereof.

In another aspect, the invention provides methods for treating a proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of Formula III.

In another aspect, the invention provides methods for treating a proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of any one or more of Formula IIIIa through Formula IIIq, andall sub-embodiments thereof.

In one aspect, the invention provides methods for treating a Raf proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of Formula I. The terms “Raf protein kinase mediated disease orcondition,” “Raf mediated disease or condition,” and the like refer to adisease or condition in which the biological function of a Raf kinase,including any mutations thereof, affects the development and/or courseof the disease or condition, and/or in which modulation of the Rafprotein kinase alters the development, course, and/or symptoms of thedisease or condition. The Raf protein kinase includes, but is notlimited to, B-Raf, mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1.In some embodiments, the Raf protein kinase is B-Raf mutation V600E. Infurther embodiments, the disease or condition is a cancer that isamenable to treatment by an inhibitor of the V600E mutant B-Raf. A Rafprotein kinase mediated disease or condition includes a disease orcondition for which Raf inhibition provides a therapeutic benefit, e.g.wherein treatment with Raf inhibitors, including compounds describedherein, provides a therapeutic benefit to the subject suffering from orat risk of the disease or condition. In one aspect, the method involvesadministering to the subject an effective amount of a compound ofFormula I in combination with one or more other therapies for thedisease or condition.

In one aspect, the invention provides methods for treating a Raf proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of Formula IIa or III. In one aspect, the method involvesadministering to the subject an effective amount of a compound ofFormula IIa or III in combination with one or more other therapies forthe disease, further wherein the compound is of Formula IIIj, IIIk, orIIIm. The Raf protein kinase includes, but is not limited to, B-Raf,mutations of B-Raf, c-Raf-1 and mutations of c-Raf-1. In someembodiments, the Raf protein kinase is B-Raf mutation V600E. In furtherembodiments, the disease or condition is a cancer that is amenable totreatment by an inhibitor of the V600E mutant B-Raf.

In one aspect, the invention provides methods for treating a Finsprotein kinase mediated disease or condition in an animal subject,wherein the method involves administering to the subject an effectiveamount of a compound of Formula I. The terms “Fms protein kinasemediated disease or condition,” “Fms mediated disease or condition,” andthe like refer to a disease or condition in which the biologicalfunction of a Fms protein kinase, including any mutations thereof,affects the development and/or course of the disease or condition,and/or in which modulation of Fms alters the development, course, and/orsymptoms of the disease or condition. A Fms mediated disease orcondition includes a disease or condition for which Fms inhibitionprovides a therapeutic benefit, e.g. wherein treatment with Fmsinhibitors, including compounds described herein, provides a therapeuticbenefit to the subject suffering from or at risk of the disease orcondition. In one aspect, the method involves administering to thesubject an effective amount of a compound of Formula I in combinationwith one or more other therapies for the disease or condition.

In one aspect, the invention provides methods for treating a Kit proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of Formula I. The terms “Kit mediated disease or condition,”“Kit protein kinase mediated disease or condition,” and the like referto a disease or condition in which the biological function of a Kitprotein kinase, including any mutation thereof, affects the developmentand/or course of the disease or condition, and/or in which modulation ofKit alters the development, course, and/or symptoms of the disease orcondition, A Kit mediated disease or condition includes a disease orcondition for which Kit inhibition provides a therapeutic benefit, e.g.wherein treatment with Kit inhibitors, including compounds describedherein, provides a therapeutic benefit to the subject suffering from orat risk of the disease or condition. In one aspect, the method involvesadministering to the subject an effective amount of a compound ofFormula I in combination with one or more other therapies for thedisease or condition.

In one aspect, the invention provides methods for treating a Jnk proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acompound of Formula I. The terms “Jnk mediated disease or condition,”“Jnk protein kinase mediated disease or condition,” and the like referto a disease or condition in which the biological function of a Jnkkinase, e.g. Jnk1, Jnk2, Jnk3, or any mutation thereof, affects thedevelopment and/or course of the disease or condition, and/or in whichmodulation of the Jnk kinase alters the development, course, and/orsymptoms of the disease or condition. A Jnk mediated disease orcondition includes a disease or condition for which Jnk inhibitionprovides a therapeutic benefit, e.g. wherein treatment with Jnkinhibitors, including compounds described herein, provides a therapeuticbenefit to the subject suffering from or at risk of the disease orcondition. In one aspect, the method involves administering to thesubject an effective amount of a compound of Formula I in combinationwith one or more other therapies for the disease or condition. The Jnkprotein kinase includes, but is not limited to, Jnk1, Jnk2, or Jnk3.

In some embodiments, a compound of Formula I will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted kinase activity assay. In some embodiments, acompound of any of Formula I will have an IC₅₀ of less than 500 nm, lessthan 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, lessthan 5 nM, or less than 1 nM with respect to at least one kinaseselected from the group consisting of Abl, Akt1, Akt2. Akt3, ALK, Alk5,B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,Flt3, Flt4, Fms, Frk, Fyn, Gsk3, Gsk3P, HCK, Her2/Erbb2, Her4/Erbb4,IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr,Kit, LCK, MAP2K1, MAP2K2. MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38,PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta,Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, IEC, Tie2, TrkA, Yes, andZap70, including any mutations thereof.

In some embodiments, a compound of Formula I will have an IC₅, of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of Abl, Akt1, Akt2, Akt3,ALK, Alk5, B-Raf, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, Fms, Fyn, Gsk3α, Gsk3β, HCK,Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3,Jnk1, Jnk2, Jnk3, Kit, LCK, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta,Plk1, Pyk2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, Yes, and Zap70,including any mutations thereof.

In some embodiments, a compound of Formula I will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of Abl, B-Raf, Btk,c-Raf-1, EGFR, EphB2, Erk2, Fak, FGFR1, Flt1, Flt3, Flt4, Fms, Irak4,Jnk1, Jnk2, Jnk3, Kdr, Kit, MAP2K1, MAPKAP kinase 2, Met, p38, PDGFRB,Pim1, PKC theta, Pyk2, Ret, Src, Stk6, Yes, and Zap70, including anymutations thereof.

In some embodiments, a compound of Formula I will have an IC₅F of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of Abl, B-Raf, Btk,c-Raf-1, EGFR, EphB2, Erk2, Fak, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kit,MAP2K1, MAPKAP kinase 2, Met, p38, Pim1, PKC theta, Pyk2, Src, Stk6,Yes, and Zap70, including any mutations thereof.

In some embodiments, a compound of Formula II will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of B-Raf, B-Raf V600Emutant, c-Raf-1. FGFR1, FGFR2. FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Met,Pim1, Pim2, Pim3, Pyk2, Kdr and Ret, including any mutations thereof.

In some embodiments, a compound of Formula III will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of B-Raf, c-Raf-1, Fms,Jnk1, Jnk2, Jnk3, and Kit, and any mutations thereof. In someembodiments, a compound of any of Formula III will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to at leastone kinase selected from the group consisting of B-Raf, B-Raf V600Emutant, c-Raf-1, Fms, Jnk1, Jnk2, Jnk3, and Kit, preferably B-Raf. B-RafV600E mutant or c-Raf-11.

In some embodiments, a compound of Formula III is an inhibitor of a Rafkinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Raf kinase activity assay. Insome embodiments, a compound of Formula III will have an IC₅₀ of lessthan 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM with respect to B-Raf,c-Raf-1, or B-Raf V600E mutant. In some embodiments, a compound ofFormula III will selectively inhibit one Raf kinase relative to one ormore other Raf kinases. In some embodiments, the compound of Formula IIIwill selectively inhibit a mutation of the Raf kinase relative to thewild type kinase, for example B-Raf V600E relative to wild type B-Raf.

In some embodiments, a compound of Formula III is an inhibitor of a Fmskinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Fms kinase activity assay. Insome embodiments, a compound of Formula III will selectively inhibit Fmskinase relative to Kit kinase.

In some embodiments, a compound of Formula III is an inhibitor of a Kitkinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Kit kinase activity assay.

In some embodiments, a compound of Formula III is an inhibitor of a Jnkkinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Jnk kinase activity assay. Insome embodiments, a compound of Formula III is an inhibitor of a Jnk1kinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Jnk1 kinase activity assay. Insome embodiments, a compound of Formula III is an inhibitor of a Jnk2kinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Jnk2 kinase activity assay. Insome embodiments, a compound of Formula III is an inhibitor of a Jnk3kinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Jnk3 kinase activity assay. Insome embodiments, a compound of Formula III will selectively inhibit oneJnk kinase relative to one or more other Jnk kinases, such asselectively inhibiting Jnk 1 relative to Jnk 2 and/or Jnk3, selectivelyinhibiting Jnk2 relative to Jnk3 and/or Jnk1, or selectively inhibitingJnk3 relative to Jnk1 and or Jnk 2.

Further to any of the above mentioned embodiments, a compound of theinvention will also inhibit the effects of a mutation of the kinase,including, but not limited to, a mutation that is related to a diseasestate, such as a cancer. For example, B-Raf V600E mutant is present in ahigh percentage of some cancers, such as melanoma, and compounds of theinvention will inhibit the kinase activity of this mutant.

Further to any of the above embodiments, a compound of the invention mayselectively inhibit one kinase relative to one or more other kinases,where preferably inhibition is selective with respect to any of theother kinases, whether a kinase discussed herein, or other kinases. Insome embodiments, the compound may selectively inhibit the effects of amutation of the kinase relative to the wild type kinase, for exampleB-Raf V600E relative to wild type B-Raf. In some embodiments, thecompound may selectively inhibit Fms relative to Kit. Selectiveinhibition of one kinase relative to another is such that the IC₅₀ forthe one kinase may be at least about 2-fold, also 5-fold, also 10-fold,also 20-fold, also 50-fold, or at least about 100-fold less than theIC₅₀ for any of the other kinases as determined in a generally acceptedkinase activity assay.

In another aspect, the invention provides compositions that include atherapeutically effective amount of a compound of Formula I and at leastone pharmaceutically acceptable carrier, excipient, and/or diluent. Thecomposition can include a plurality of different pharmacologicallyactive compounds, which can include a plurality of compounds of FormulaI. In another aspect, the composition can include one or more compoundsof Formula I, Formula II, or Formula III along with one or morecompounds that are therapeutically effective for the same diseaseindication. In one aspect, the composition includes one or morecompounds of Formula I, Formula II, or Formula III along with one ormore compounds that are therapeutically effective for the same diseaseindication, wherein the compounds have a synergistic effect on thedisease indication.

In another aspect, the invention provides compositions that include atherapeutically effective amount of at least one compound of Formula IIIand at least one pharmaceutically acceptable carrier, excipient, and/ordiluent. The composition can include a plurality of differentpharmacologically active compounds, which can include a plurality ofcompounds of Formula III, or can include at least one compound ofFormula III along with at least one compound that is therapeuticallyeffective for the same disease indication. In one aspect, the at leastone compound of Formula III and the at least one compound that istherapeutically effective for the same disease indication have asynergistic effect on the disease indication. In one aspect, thecomposition includes one or more compounds of Formula III effective intreating a cancer and one or more other compounds that are effective intreating the cancer, further wherein the compounds are synergisticallyeffective in treating the cancer.

In another aspect, the invention provides a method for modulating theactivity of a protein kinase selected from the group consisting of Abl,Akt1, Akt2, Akt3, ALK, Alk5, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6,CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1,FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3r, Gsk3J, HCK,Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3,Jnk1, Jnk2, Jnk3, Kdr, Kit, LCK, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met,Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKCbeta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC,Tie2, TrkA, Yes, or Zap70 by contacting the protein kinase with aneffective amount of a compound of Formula I.

In another aspect, the invention provides methods for treating a proteinkinase mediated disease or condition in an animal subject, wherein themethod involves administering to the subject an effective amount of acomposition including a compound of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, B-Raf, Btk, Cdk2, CDK4,CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2,Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Fyn, Gsk3α,Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1,Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, LCK, MAP2K1, MAP2K2, MAP4K4,MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3,PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src,Stk6, Syk, TEC, Tie2, TrkA, Yes, and Zap70 by administering to thesubject an effective amount of a composition including a compound ofFormula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, B-Raf, Btk, Cdk2, CDK4,CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2,Fak, Fms, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKKbeta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kit, LCK, MAP2K1,MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDPK1, Pim1, Pim2, Pim3,PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, Ron, Src, Stk6, Syk, TEC,Tie2, TrkA, Yes, and Zap70 by administering to the subject an effectiveamount of a composition including a compound of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of Abl, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak, FGFR1,Flt1, Flt3, Flt4, Fms, Irak4, Jnk1, Jnk2, Jnk3, Kdr, Kit, MAP2K1,MAPKAPK2, Met, p38, PDGFRB, Pim1, PKC theta, Pyk2, Ret, Src, Stk6, Yes,and Zap70 by administering to the subject an effective amount of acomposition including a compound of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of Abl, B-Raf, Btk, c-Raf-1, EGFR, EphB2, Erk2, Fak, Fms,Irak4, Jnk1, Jnk2, Jnk3, Kit, MAP2K1, MAPKAPK2, Met, p38, Pim1, PKCtheta, Pyk2, Src, Stk6, Yes, and Zap70 by administering to the subjectan effective amount of a composition including a compound of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of B-Raf, B-Raf V600E mutant, c-Raf-1, FGFR1, FGFR2, FGFR3,FGFR4, Jnk1, Jnk2, Jnk3, Met, Pim1, Pim2, Pim3, Pyk2, Kdr and Ret byadministering to the subject an effective amount of a compositionincluding a compound of Formula I.

In one aspect, the invention provides methods for treating a disease orcondition mediated by a protein kinase selected from the groupconsisting of B-Raf, c-Raf-1, Fms, Jnk1, Jnk2, Jnk3, and Kit, and anymutations thereof, by administering to the subject an effective amountof a composition including a compound of Formula III.

In one aspect, the invention provides methods for treating a disease orcondition mediated by B-Raf, c-Raf-1, or B-Raf V600E by administering tothe subject an effective amount of a composition including a compound ofFormula II or Formula III, where in further embodiments, the compound isof Formula IIa or Formula III. In one aspect, the invention providesmethods for treating a disease or condition mediated by B-Raf, c-Raf-1,or B-Raf V600E by administering to the subject an effective amount of acomposition including a compound of Formula IIIj, IIIk, or IIIm incombination with one or more other suitable therapies for treating thedisease. In one aspect, the invention provides methods for treating acancer mediated by B-Raf V600E mutant by administering to the subject aneffective amount of a composition of Formula IIIj, IIIk, or IIIm incombination with one or more suitable anticancer therapies, such as oneor more chemotherapeutic drugs.

In one aspect, the invention provides a method of treating a cancer byadministering to the subject an effective amount of a compositionincluding a compound of Formula I, or where the compound is of FormulaIII, or where the compound is of Formula IIIj, IIIk, or IIIm, incombination with one or more other therapies or medical procedureseffective in treating the cancer. Other therapies or medical proceduresinclude suitable anticancer therapy (e.g. drug therapy, vaccine therapy,gene therapy, photodynamic therapy) or medical procedure (e.g. surgery,radiation treatment, hyperthermia heating, bone marrow or stem celltransplant). In one aspect, the one or more suitable anticancertherapies or medical procedures is selected from treatment with achemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment(e.g. x-ray, γ-ray, or electron, proton, neutron, or a particle beam),hyperthermia heating (e.g. microwave, ultrasound, radiofrequencyablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinomavaccine, AFP adenoviral vector vaccine, AG-858, allogeneicGM-CSF-secretion breast cancer vaccine, dendritic cell peptidevaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encodingMDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy(e.g. aminolevulinic acid, motexafin lutetium), surgery, and bone marrowand stem cell transplantation.

In a preferred embodiment, the invention provides a method of treating acancer by administering to the subject an effective amount of acomposition including a compound of Formula I, or wherein the compoundis of Formula III, or wherein the compound is of Formula IIIj, IIIk, orIIIm, in combination with one or more suitable chemotherapeutic agents.In one aspect, the one or more suitable chemotherapeutic agents isselected from an alkylating agent, including, but not limited to,adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone,carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine,estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan,irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin,piposulfan, semustine, streptozocin, temozolomide, thiotepa, andtreosulfan; an antibiotic, including, but not limited to, bleomycin,dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin,menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, andplicamycin; an antimetabolite, including, but not limited to,azacitidine, capecitabine, cladribine, clofarabine, cytarabine,decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur,gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine,pemetrexed, raltitrexed, thioguanine, and trimetrexate; animmunotherapy, including, but not limited to, alemtuzumab, bevacizumab,cetuximab, galiximab, gemtuzamab, panitumumab, pertuzumab, rituximab,tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; a hormone orhormone antagonist, including, but not limited to, anastrozole,androgens, buserelin, diethylstilbestrol, exemestane, flutamide,fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol,raloxifene, tamoxifen, and toremifene; a taxane, including, but notlimited to, DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; aretinoid, including, but not limited to, alitretinoin, bexarotene,fenretinide, isotretinoin, and tretinoin; an alkaloid, including, butnot limited to, etoposide, homoharringtonine, teniposide, vinblastine,vincristine, vindesine, and vinorelbine; an antiangiogenic agent,including, but not limited to, AE-941 (GW786034, Neovastat), ABT-510,2-methoxyestradiol, lenalidomide, and thalidomide; a topoisomeraseinhibitor, including, but not limited to, amsacrine, edotecarin,exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan, and9-aminocamptothecin; a kinase inhibitor, including, but not limited to,erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib,sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107,BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), and vatalanib;a targeted signal transduction inhibitor including, but not limited tobortezomib, geldanamycin, and rapamycin; a biological response modifier,including, but not limited to, imiquimod, interferon-α, andinterleukin-2; and other chemotherapeutics, including, but not limitedto 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),aminoglutethimide, asparaginase, bryostatin-1, cilengitide, E7389,ixabepilone, procarbazine, sulindac, temsirolimus, tipifarnib.Preferably, the method of treating a cancer involves administering tothe subject an effective amount of a composition of Formula I (morepreferably Formula II, and even more preferably Formulae IIIj, IIIk, orIIIm) in combination with a chemotherapeutic agent selected from5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, orerlotinib.

In another aspect, the invention provides a method of treating orprophylaxis of a disease or condition in a mammal, by administering tothe mammal a therapeutically effective amount of a compound of FormulaI, a prodrug of such compound, or a pharmaceutically acceptable salt ofsuch compound or prodrug. The compound can be alone or can be part of acomposition. In another aspect, the invention provides a method oftreating or prophylaxis of a disease or condition in a mammal, byadministering to the mammal a therapeutically effective amount of acompound of Formula III, a prodrug of such compound, or apharmaceutically acceptable salt of such compound or prodrug incombination with one or more other suitable therapies for the disease orcondition.

In another aspect, the invention provides compositions that include atherapeutically effective amount of a compound of Formula III and atleast one pharmaceutically acceptable carrier, excipient, and/ordiluent. The composition can include a plurality of differentpharmacologically active compounds, which can include a plurality ofcompounds of Formula III.

In a related aspect, the invention provides kits that include acomposition as described herein. In some embodiments, the composition ispackaged, e.g., in a vial, bottle, flask, which may be further packaged,e.g., within a box, envelope, or bag; the composition is approved by theU.S. Food and Drug Administration or similar regulatory agency foradministration to a mammal, e.g., a human; the composition is approvedfor administration to a mammal, e.g., a human, for a protein kinasemediated disease or condition; the invention kit includes writteninstructions for use and/or other indication that the composition issuitable or approved for administration to a mammal, e.g., a human, fora protein kinase-mediated disease or condition; and the composition ispackaged in unit dose or single dose form, e.g., single dose pills,capsules, or the like.

In aspects involving treatment or prophylaxis of a disease or conditionwith the compounds of Formula I, the disease or condition is, forexample without limitation, neurologic diseases such as ischemic stroke,cerebrovascular ischemia, multi-infarct dementia, head injury, spinalcord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophiclateral sclerosis, dementia, senile chorea, and Huntington's disease:neoplastic diseases and associated complications, includingchemotherapy-induced hypoxia, gastrointestinal stromal tumors (GISTs),prostate tumors, mast cell tumors (including canine mast cell tumors),acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloidleukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma,mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma,sarcomas (e.g. sarcomas of neuroectodermal origin, leiomyosarcoma),carcinomas (e.g. lung, breast, pancreatic, colon, hepatocellular, renal,female genital tract, squamous cell, carcinoma in situ), lymphoma (e.g.histiocytic lymphoma, non-Hodgkin's lymphoma), MEN2 syndromes,neurofibromatosis (including Schwann cell neoplasia), myclodysplasticsyndrome, leukemia, tumor angiogenesis, and cancers of the thyroid,liver, bone, skin, brain, central nervous system, pancreas, lung (e.g.small cell lung cancer, non small cell lung cancer), breast, colon,bladder, prostate, gastrointestinal tract, endometrium, fallopian tube,testes and ovary; pain of neuropathic or inflammatory origin, includingacute pain, chronic pain, and migraine; cardiovascular diseasesincluding heart failure, cardiac hypertrophy, thrombosis (e.g.thrombotic microangiopathy syndromes), atherosclerosis, reperfusioninjury and ischemia (e.g. cerebrovascular ischemia, liver ischemia);inflammation including, but not limited to, polycystic kidney disease(PKD), age-related macular degeneration, rheumatoid arthritis, allergicrhinitis, inflammatory bowel disease (IBD), ulcerative colitis, Crohn'sdisease, systemic lupus erythematosis, Sjogren's Syndrome, Wegener'sgranulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave'sdisease, myasthenia gravis, multiple sclerosis, osteoarthritis,endometriosis, scarring (e.g. dermal, tissue), vascular restenosis,fibrotic disorders, hypereosinophilia, CNS inflammation, pancreatitis,nephritis, atopic dermatitis, and hepatitis; immunodeficiency diseases(e.g. severe combined immunodeficiency (SCID)), organ transplantrejection, graft versus host disease; renal or prostatic diseasesincluding diabetic nephropathy, nephrosclerosis, glomerulonephritis,interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronicrenal failure, tubular necrosis, diabetes-associated renalcomplications, and hypertrophy; metabolic diseases including type 1diabetes, type 2 diabetes, metabolic syndrome, obesity, hepaticsteatosis, insulin resistance, hyperglycemia, lipolysis and obesity;infection, including, but not limited to Helicobacter pylori andInfluenza virus, fever, sepsis; pulmonary diseases including chronicobstructive pulmonary disease (COPD), acute respiratory distresssyndrome (ARDS), asthma, allergy, bronchitis, emphysema, and pulmonaryfibrosis; genetic developmental diseases such as Noonan's syndrome,Crouzon syndrome, acrocephalo-syndactyl)-type I, Pfeiffer's syndrome,Jackson-Weiss syndrome, Costello syndrome, (faciocutaneoskeletalsyndrome), leopard syndrome, cardio-faciocutaneous syndrome (CFC) andneural crest syndrome abnormalities causing cardiovascular, skeletal,intestinal, skin, hair and endocrine diseases; disorders of bonestructure or mineralization, including osteoporosis, increased risk offracture, hypercalcemia, and bone metastases; Grave's disease;Hirschsprung's disease; lymphodema; selective T-cell defect (STD);X-linked agammaglobulinemia; diabetic retinopathy; alopecia; erectiledysfunction; and tuberous sclerosis.

In a related aspect, compounds of Formula I, further where the compoundis of Formula III, can be used in the preparation of a medicament forthe treatment of a B-Raf-mediated disease or condition, selected fromthe group consisting of neurologic diseases such as ischemic stroke,multi-infarct dementia, head injury, spinal cord injury, Alzheimer'sdisease (AD), Parkinson's disease; neoplastic diseases including, butnot limited to, melanoma, glioma, sarcoma, carcinoma (e.g. lung, breast,pancreatic, renal), lymphoma (e.g. histiocytic lymphoma) and cancer ofthe thyroid, lung (e.g. small cell lung cancer), liver, breast, ovaryand colon, neurofibromatosis, myelodysplastic syndrome, leukemia, tumorangiogenesis; pain of neuropathic or inflammatory origin, includingacute pain, chronic pain, and migraine; cardiovascular diseasesincluding heart failure, cardiac hypertrophy, thrombosis (e.g.thrombotic microangiopathy syndromes), atherosclerosis, reperfusioninjury; inflammation including, but not limited to, psoriasis,polycystic kidney disease (PKD), arthritis and autoimmune diseases andconditions, osteoarthritis, endometriosis, scarring, vascularrestenosis, fibrotic disorders, rheumatoid arthritis, inflammatory boweldisease (IBD); immunodeficiency diseases, organ transplant rejection,graft versus host disease; renal or prostatic diseases includingdiabetic nephropathy, nephrosclerosis, glomerulonephritis, prostatehyperplasia; metabolic disorders, obesity; infection, including, but notlimited to Helicobacter pylori and Influenza virus, fever, sepsis;pulmonary diseases including chronic obstructive pulmonary disease(COPD) and acute respiratory distress syndrome (ARDS); geneticdevelopmental diseases such as Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), leopard syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases.

In a related aspect, compounds of Formula III, further where thecompound is of Formula III, can be used in the preparation of amedicament for the treatment of a c-Raf-1-mediated disease or conditionselected from the group consisting of colorectal, ovarian, lung andrenal cell carcinoma, acute myeloid leukemia, myclodysplastic syndromes,tumor angiogenesis, and neuroendocrine tumors such as medullary thyroidcancer, carcinoid, small cell lung cancer and pheochromocytoma.

In a related aspect, compounds of Formula III, further where thecompound is of Formula III, can be used in the preparation of amedicament for the treatment of a Fms-mediated disease or conditionselected from the group consisting of immune disorders, includingrheumatoid arthritis, systemic lupus erythematosis (SLE), Wegener'sgranulomatosis, and transplant rejection, inflammatory diseasesincluding Chronic Obstructive Pulmonary Disease (COPD), emphysema, andatherosclerosis, metabolic disorders, including insulin resistance,hyperglycemia, and lipolysis, disorders of bone structure ormineralization, including osteoporosis, increased risk of fracture,hypercalcemia, and hone metastases, kidney diseases, including nephritis(e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis),tubular necrosis, diabetes-associated renal complications, andhypertrophy and cancers, including multiple myeloma, acute myeloidleukemia, chronic myeloid leukemia (CML), breast cancer, and ovariancancer.

In a related aspect, compounds of Formula II, further where the compoundis of Formula III, can be used in the preparation of a medicament forthe treatment of a Jnk-mediated disease or condition selected from thegroup consisting of metabolic diseases including type 1 diabetes, type 2diabetes, metabolic syndrome, obesity, and hepatic steatosis;cardiovascular diseases such as atherosclerosis, ischemia (e.g.cerebrovascular ischemia, liver ischemia), reperfusion injury, cardiachypertrophy; renal diseases such as chronic renal failure; neoplasticdiseases and associated complications, including chemotherapy-inducedhypoxia, prostate tumors, myeloid leukemia and cancers of the liver,bone, skin, brain, pancreas, lung breast, colon, prostate and ovary;transplant rejection; pain of neuropathic or inflammatory originincluding acute and chronic pain; inflammatory and autoimmune diseasesincluding age-related macular degeneration, rheumatoid arthritis,inflammatory bowel disease, ulcerative colitis, Crohn's disease,systemic lupus erythematosis, Sjogren's Syndrome, psoriasis,scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis,and multiple sclerosis, and inflammation in other organs including CNSinflammation, pancreatitis, nephritis, atopic dermatitis, and hepatitis;airway inflammatory diseases such as asthma, allergy, bronchitis,pulmonary fibrosis, chronic obstructive pulmonary disease; neurologicdiseases such as stroke, cerebrovascular ischemia, neurodegenerativediseases such as Parkinson's disease, Alzheimer's disease, amyotrophiclateral sclerosis, dementia, senile chorea, head and spinal cord trauma,and Huntington's disease.

In a related aspect, compounds of Formula III, further where thecompound is of Formula III, can be used in the preparation of amedicament for the treatment of a Jnk1-mediated disease or conditionselected from the group consisting of type 1 diabetes, type 2 diabetes,metabolic syndrome, obesity and hepatic steatosis.

In a related aspect, compounds of Formula III, further where thecompound is of Formula III, can be used in the preparation of amedicament for the treatment of a Jnk2-mediated disease or condition,such as atherosclerosis.

In a related aspect, compounds of Formula III, further where thecompound is of Formula III, can be used in the preparation of amedicament for the treatment of a Jnk3-mediated disease or conditionselected from the group consisting of inflammatory diseases includingautoimmune diseases such as rheumatoid arthritis, inflammatory bowelsyndrome, Crohn's disease, systemic lupus erythematosis, Sjogren'sSyndrome, psoriasis and multiple sclerosis, airway inflammatory diseasessuch as asthma, allergy, pulmonary fibrosis, and chronic obstructivepulmonary disease, and inflammation in other organs, such as CNSinflammation, pancreatitis, nephritis, and hepatitis; neurologicdiseases such as stroke, cerebrovascular ischemia, and neurodegenerativediseases such as Parkinson's disease, Alzheimer's disease, andHuntington's disease; and neoplastic diseases such as prostate tumorsand myeloid leukemia.

In a related aspect, compounds of Formula II, further where the compoundis of Formula III, can be used in the preparation of a medicament forthe treatment of a Kit-mediated disease or condition selected from thegroup consisting of malignancies, including mast cell tumors, small celllung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs),glioblastoma, astrocytoma, neuroblastoma, carcinomas of the femalegenital tract, sarcomas of neuroectodermal origin, colorectal carcinoma,carcinoma in situ, Schwann cell neoplasia associated withneurofibromatosis, acute myelocytic leukemia, acute lymphocyticleukemia, chronic myelogenous leukemia, mastocytosis, melanoma, andcanine mast cell tumors, and inflammatory diseases, including asthma,rheumatoid arthritis, allergic rhinitis, multiple sclerosis,inflammatory bowel syndrome, transplant rejection, andhypereosinophilia.

The compounds of Formula I with kinase activity IC₅₀ less than 10 μM asdetermined in a standard assay described herein can be used to treatprotein kinase mediated diseases and conditions related to the followingprotein kinases, for example without limitation:

-   -   Abl, related to chronic myeloid leukemia (CML), acute        lymphoblastic leukemia (ALL) and acute myelogenous leukemia        (AML);    -   Akt1, related to gastric, prostate, colorectal, ovarian,        pancreatic and breast cancer, glioblastoma and leukemia, as well        as schizophrenia and bipolar disorders, and also use in        combination with other chemotherapeutic drugs;    -   Akt2, related to hyperglycemia due to peripheral insulin        resistance and nonsuppressible hepatic glucose production        accompanied by inadequate compensatory hyperinsulinemia, also        related to pancreatic, ovarian and breast cancer;    -   Akt3, related to melanoma, prostate and breast cancer;    -   ALK, related to non-Hodgkin lymphomas such as diffuse large        B-cell lymphoma and anaplastic large cell lymphoma;    -   Alk5, related to pancreatic and biliary cancers, and cutaneous        T-cell lymphoma;    -   B-Raf, related to neurologic diseases such as ischemic stroke,        multi-infarct dementia, head injury, spinal cord injury,        Alzheimer's disease (AD), Parkinson's disease; neoplastic        diseases including, but not limited to, melanoma, glioma,        sarcoma, carcinoma (e.g. lung, breast, pancreatic, renal),        lymphoma (e.g. histiocytic lymphoma) and cancer of the thyroid,        lung (e.g. small cell lung cancer), liver, breast, ovary and        colon, neurofibromatosis, myelodysplastic syndrome, leukemia,        tumor angiogenesis; pain of neuropathic or inflammatory origin,        including acute pain, chronic pain, and migraine; cardiovascular        diseases including heart failure, cardiac hypertrophy,        thrombosis (e.g. thrombotic microangiopathy syndromes),        atherosclerosis, reperfusion injury; inflammation including, but        not limited to, psoriasis, polycystic kidney disease (PKD),        arthritis and autoimmune diseases and conditions,        osteoarthritis, endometriosis, scarring, vascular restenosis,        fibrotic disorders, rheumatoid arthritis, inflammatory bowel        disease (IBD); immunodeficiency diseases, organ transplant        rejection, graft versus host disease; renal or prostatic        diseases including diabetic nephropathy, nephrosclerosis,        glomerulonephritis, prostate hyperplasia; metabolic disorders,        obesity; infection, including, but not limited to Helicobacter        pylori and Influenza virus, fever, sepsis; pulmonary diseases        including chronic obstructive pulmonary disease (COPD) and acute        respiratory distress syndrome (ARDS); genetic developmental        diseases such as Noonan's syndrome, Costello syndrome,        (faciocutaneoskeletal syndrome), leopard syndrome,        cardio-faciocutaneous syndrome (CFC), and neural crest syndrome        abnormalities causing cardiovascular, skeletal, intestinal,        skin, hair and endocrine diseases;    -   c-Raf-1, related to colorectal, ovarian, lung and renal cell        carcinoma, acute myeloid leukemia, myclodysplastic syndromes,        tumor angiogenesis, and neuroendocrine tumors such as medullary        thyroid cancer, carcinoid, small cell lung cancer and        pheochromocytoma;    -   Brk, related to breast and colon cancer, and head and neck        squamous cell carcinoma;    -   Btk, related to X-linked agammaglobulinemia, acute lymphocytic        leukemia, autoimmune diseases such as multiple sclerosis,        systemic lupus erythematosis, rheumatoid arthritis, and Graves'        disease, immune suppression in organ transplant, and drug        sensitivity of B-lineage cells;    -   Cdk2, related to prostate, breast, colorectal and ovarian        cancer;    -   Cdk4, related to glioblastoma (e.g. glioblastoma multiforme),        anaplastic astrocytoma, and breast cancer;    -   Cdk5, related to Alzheimer's disease, amyotrophic lateral        sclerosis and Lewy body disease;    -   Cdk6, related to glioblastoma multiforme, non-Hodgkin's        lymphoma, splenic marginal zone lymphoma, T-cell lymphoblastic        lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia        (T-ALL);    -   CHK1, related to DNA damage repair, sensitizes cells to        chemotherapeutic agents;    -   Csk, related to colon and pancreatic carcinomas and autoimmune        pathology such as type 1 diabetes, rheumatoid arthritis and        systemic lupus erythematosus;    -   EGFR, related to breast, colorectal, bladder, prostate and non        small cell lung cancer, squamous cell carcinomas of the head and        neck cancer, oral cavity, and esophagus, and glioblastoma        multiforme;    -   EphA1, related to head and neck squamous cell carcinoma,        hepatoma and lung cancer;    -   EphA2, related to aberrant short-range contact-mediated axonal        guidance, bladder, breast, prostate, colon, skin, cervical,        ovarian, pancreatic and lung cancers, and metastatic melanoma;    -   EphB2, related to angiogenesis disorder (e.g. ocular        angiogenesis disease such as retinopathy), and cancer (e.g.        glioblastoma, breast and liver cancer);    -   EphB4, related to colorectal cancer (CRC), head and neck        squamous cell carcinoma, and tumours of the prostate, breast,        endometrium, and bladder;    -   Erk2, related to aberrant proliferation, differentiation,        transcription regulation and development, and may be useful in        treating inflammation, for example inflammation associated with        Lyme neuroborreliosis, and in treating cancers, such as gastric        cancer;    -   Fak, related to colon and breast tumors, and is also related to        esophageal squamous cell carcinoma, melanoma, anaplastic        astrocytoma, glioblastoma, ductal carcinoma in situ, prostate        and hepatocellular carcinoma, and tumor metastases, and may also        provide synergistic effects when used with other        chemotherapeutic drugs;    -   FGFR1, related to 8p11 myeloproliferative syndrome;    -   FGFR2, related to Crouzon Syndrome, Jackson-Weiss Syndrome,        Apert Syndrome, craniosynostosis, Pfeiffer Syndrome, aerocephalo        syndactyly type V, and Beare-Stevenson Cutis Gyrata Syndrome;    -   FGFR3, related to angiogenesis, wound healing, achondroplasia,        Muenke craniosynostosis, Crouzon syndrome, acanthosis nigricans,        thanatophoric dysplasia, bladder carcinomas, and multiple        myeloma;    -   FGFR4, related to cancer of the breast, lung, colon, medullary        thyroid, pancreas, ovary, prostate, endometrium, and fallopian        tube, head and neck squamous cell carcinomas and leiomyosarcoma;    -   Flt1, related to non-small cell lung carcinoma, prostate        carcinoma, and colorectal cancer;    -   Flt3, related to acute myeloid leukemia, myelodysplastic        syndrome, acute lymphoblastic leukemia;    -   Flt4, related to primary lymphoedema;    -   Fms, related to immune disorders, including rheumatoid        arthritis, systemic lupus erythematosis (SLE), Wegener's        granulomatosis, and transplant rejection, inflammatory diseases        including Chronic Obstructive Pulmonary Disease (COPD),        emphysema, and atherosclerosis, metabolic disorders, including        insulin resistance, hyperglycemia, and lipolysis, disorders of        bone structure or mineralization, including osteoporosis,        increased risk of fracture, hypercalcemia, and bone metastases,        kidney diseases, including nephritis (e.g. glomerulonephritis,        interstitial nephritis, Lupus nephritis), tubular necrosis,        diabetes-associated renal complications, and hypertrophy and        cancers, including multiple myeloma, acute myeloid leukemia,        chronic myeloid leukemia (CML), breast cancer, and ovarian        cancer;    -   Frk, related to acute myeloid leukemia and type 1 diabetes;    -   Fyn, related to Alzheimer's disease, schizophrenia and        prevention of metastases, e.g. in melanoma and squamous cell        carcinoma;    -   GSK3 (Gsk3a and/or Gsk3β), related to CNS disorders such as        Alzheimer's disease. Parkinson's disease, amyotrophic lateral        sclerosis, diabetes type II, bipolar disorders, stroke, cancer,        chronic inflammatory disease, leukopenia, schizophrenia, chronic        pain, neuropathic pain, and traumatic head injury;    -   HCK, related to chronic myelogenous leukemia and acute        lymphocytic leukemia;    -   Her2/Erbb2, related to prostate and breast cancer;    -   Her4/Erbb4, related to childhood medulloblastoma;    -   IGF1R, related to prostate cancer, hepatocellular carcinoma;    -   IKK beta, related to leukemia of T-cells, necrosis, insulin        resistance, and malignant neoplasms;    -   Irak4, related to bacterial infections, immunodeficiency        syndrome, Crohn's disease, ulcerative colitis, asthma, chronic        bronchitis, cardio hypertrophy, and kidney hypertension;    -   Itk, related to allergic asthma;    -   Jak1, related to Hepatitis C virus infection;    -   Jak2, related to myeloproliferative disorders such as        polycythemia vera, myelofibrosis, essential thrombocythemia,        myeloid metaplasia and leukemias, including acute lymphoblastic        leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic        leukemia, CMML, Philadelphia chromosome-negative CML,        megakaryocytic leukemia, and acute erythroid leukemia;    -   Jak3, related to X-linked severe combined immunodeficiency,        myeloproliferative disorders, transplant rejection and        autoimmune diseases such as rheumatoid arthritis, inflammatory        bowel syndrome, Crohn's disease, systemic lupus erythematosis,        ulcerative colitis, psoriasis and multiple sclerosis;    -   Jnk (Jnk1, Jnk2, Jnk3), related to metabolic diseases including        type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity,        and hepatic steatosis; cardiovascular diseases such as        atherosclerosis, ischemia (e.g. cerebrovascular ischemia, liver        ischemia), reperfusion injury, cardiac hypertrophy; renal        diseases such as chronic renal failure; neoplastic diseases and        associated complications, including chemotherapy-induced        hypoxia, prostate tumors, myeloid leukemia and cancers of the        liver, bone, skin, brain, pancreas, lung breast, colon, prostate        and ovary; transplant rejection; pain of neuropathic or        inflammatory origin including acute and chronic pain;        inflammatory and autoimmune diseases including age-related        macular degeneration, rheumatoid arthritis, inflammatory bowel        disease, ulcerative colitis, Crohn's disease, systemic lupus        erythematosis, Sjogren's Syndrome, psoriasis, scleroderma,        chronic thyroiditis, Grave's disease, myasthenia gravis, and        multiple sclerosis, and inflammation in other organs including        CNS inflammation, pancreatitis, nephritis, atopic dermatitis,        and hepatitis; airway inflammatory diseases such as asthma,        allergy, bronchitis, pulmonary fibrosis, chronic obstructive        pulmonary disease; neurologic diseases such as stroke,        cerebrovascular ischemia, neurodegenerative diseases such as        Parkinson's disease, Alzheimer's disease, amyotrophic lateral        sclerosis, dementia, senile chorea, head and spinal cord trauma,        and Huntington's disease. More particularly, Jnk1 is related to        type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity        and hepatic steatosis, Jnk2 is related to atherosclerosis, and        Jnk3 is related to inflammatory diseases including autoimmune        diseases such as rheumatoid arthritis, inflammatory bowel        syndrome, Crohn's disease, systemic lupus erythematosis,        Sjogren's Syndrome, psoriasis and multiple sclerosis, airway        inflammatory diseases such as asthma, allergy, pulmonary        fibrosis, and chronic obstructive pulmonary disease, and        inflammation in other organs, such as CNS inflammation,        pancreatitis, nephritis, and hepatitis; neurologic diseases such        as stroke, cerebrovascular ischemia, and neurodegenerative        diseases such as Parkinson's disease, Alzheimer's disease, and        Huntington's disease; and neoplastic diseases such as prostate        tumors and myeloid leukemia;    -   Kdr, related to anti-angiogenesis for treating solid tumor        growth (e.g. ovarian, lung, breast, pancreatic, prostate, colon,        gastrointestinal stromal tumor, non small cell lung cancer, and        epidermoid cancer), metastasis, psoriasis, rheumatoid arthritis,        diabetic retinopathy and age related macular degeneration;    -   Kit, related to malignancies, including mast cell tumors, small        cell lung cancer, testicular cancer, gastrointestinal stromal        tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma,        carcinomas of the female genital tract, sarcomas of        neuroectodermal origin, colorectal carcinoma, carcinoma in situ,        Schwann cell neoplasia associated with neurofibromatosis, acute        myelocytic leukemia, acute lymphocytic leukemia, chronic        myelogenous leukemia, mastocytosis, melanoma, and canine mast        cell tumors, and inflammatory diseases, including asthma,        rheumatoid arthritis, allergic rhinitis, multiple sclerosis,        inflammatory bowel syndrome, transplant rejection, and        hypereosinophilia;    -   LCK, related to acute lymphoblastic leukemia, T-cell lymphoma,        lymphopenia, renal carcinoma, colon carcinoma, severe combined        immunodeficiency, multiple sclerosis, inflammatory bowel and        type I diabetes;    -   MAP2K1, related to acute myeloid leukemia, breast, ovarian and        liver cancer;    -   MAP2K2, related to cancer and inflammation:    -   MAP4K4, related to cancer and tumor metastasis, diabetes and        metabolic syndrome;    -   MAPKAPK2, cancer (e.g. prostate, breast), stroke, meningitis,        and inflammatory disorders;    -   Met, related to kidney, breast, bladder, non-small-cell lung,        colorectal, and bladder cancers, and hepatocellular carcinoma;    -   Mnk1, related to conditions associated with heat shock, nutrient        deprivation, oxidative or osmotic stress, and infection of        mammalian cells (e.g. with viruses such as adenovirus (Ad) or        influenza virus), and autoimmune diseases;    -   MLK1, related to neurodegenerative diseases such as Alzheimer's        disease and Parkinson's disease, and inflammatory disorders;    -   p38, related to acute coronary syndrome, stroke,        atherosclerosis, and inflammatory autoimmune diseases such as        rheumatoid arthritis, inflammatory bowel disease, and Crohn's        disease;    -   PDGFR (PDGFRA, PDGFRB), related to idiopathic hypereosinophilic        syndrome, chronic eosinophilic leukemia, glioma,        gastrointestinal stromal tumors (GISTs), juvenile myelomonocytic        leukemia, metastatic medulloblastoma, atherogenesis, and        restenosis. More particularly, PDGFRA related to idiopathic        hypereosinophilic syndrome, chronic eosinophilic leukemia,        glioma, gastrointestinal stromal tumors (GISTs), juvenile        myelomonocytic leukemia, metastatic medulloblastoma,        atherogenesis, and restenosis, and PDGFRB related to idiopathic        hypereosinophilic syndrome, chronic eosinophilic leukemia,        juvenile myelomonocytic leukemia, and metastatic        medulloblastoma;    -   PDPK1, related to cancer and diabetes;    -   Pim1, related to cancers such as hematopoietic (e.g. acute        myeloid and acute lymphoid leukemias) and prostate cancers, and        non-Hodgkin's lymphomas;    -   Pim2, related to lymphomas;    -   Pim3, related to hepatocellular carcinoma;    -   PKC alpha, related to pituitary tumors and prefrontal cortical        dysfunction such as distractibility, impaired judgment,        impulsivity, and thought disorder, also may be used to sensitize        chemotherapy in breast, colon, and non small cell lung cancers;    -   PKC beta, related to diabetic retinopathy;    -   PKC-theta, related to insulin resistance, T-cell lymphoma;    -   Plk1, related to cancers (e.g. lymphoma of the thyroid,        non-Hodgkin's lymphomas, colorectal cancers, leukemias and        melanoma), also useful as sensitizer in chemotherapy;    -   Pyk2, related to inflammation (e.g. osteoporosis, polycystic        kidney disease, rheumatoid arthritis and inflammatory bowel        disease), CNS disease (e.g. Parkinson's disease and Alzheimer's        disease), stroke and cancers (e.g. gliomas, breast cancer, and        pancreatic cancer):    -   Ret, related to cancer of the thyroid, neuroblastoma, familial        medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia        type IIA and IIB (MEN2A, MEN2B), and neurodegenerative disorders        (e.g. Hirschsprung's disease, Parkinson's disease, Alzheimer's        disease, and amyotrophic lateral sclerosis);    -   ROCK (ROCK-1, ROCK-2), related to cancers (e.g. ovarian cancer,        hepatocellular carcinoma, pancreatic cancer), ocular disease        (e.g. glaucoma), cardiac hypertrophy, improved renal perfusion,        transplant rejection, and acute respiratory distress syndrome;    -   Ron, related to cancer and inflammation;    -   Src, related to cancer and osteoporosis;    -   Stk6, related to gastric, bladder, breast, lung, CNS, ovarian,        kidney, colon, prostate, pancreas, and cervical cancers,        melanoma, leukemia, and neuroblastoma;    -   Syk, related to lymphomas (e.g. mantle cell lymphoma);    -   TEC, related to sepsis, septic shock, inflammation, rheumatoid        arthritis, Crohn's disease, irritable bowel disease (IBD), and        ulcerative colitis;    -   Tie2 (TEK), related to cancer, arthritis (e.g. rheumatoid        arthritis), and atherosclerosis;    -   TrkA, related to pain (e.g. chronic pain, neuropathic pain),        cancer, arthritis, diabetic retinopathy, macular degeneration        and psoriasis;    -   Yes, related to various cancers including esophageal squamous        cell carcinoma; and    -   Zap70, related to AIDS, systemic lupus erythematosus, myasthenia        gravis, atherosclerosis, rejection of transplanted organs or        tissues, allograft rejection including acute and chronic        allograft rejection, graft versus host disease, rheumatoid        arthritis, psoriasis, systemic sclerosis, atopic dermatitis,        eczematous dermatitis, alopecia, and inflammation of the nasal        mucus membrane, including all forms of rhinitis.

Additional aspects and embodiments will be apparent from the followingDetailed Description and from the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the following definitions apply unless clearly indicatedotherwise:

“Halogen” refer to all halogens, that is, chloro (Cl), fluoro (F), bromo(Br), or iodo (I).

“Hydroxyl” or “hydroxy” refer to the group —OH.

“Thiol” refers to the group —SH.

“Lower alkyl” alone or in combination means an alkane-derived radicalcontaining from 1 to 6 carbon atoms (unless specifically defined) thatincludes a straight chain alkyl or branched alkyl. The straight chain orbranched alkyl group is attached at any available point to produce astable compound. In many embodiments, a lower alkyl is a straight orbranched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.A “substituted lower alkyl” denotes lower alkyl that is independentlysubstituted, unless indicated otherwise, with one or more, preferably 1,2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any availableatom to produce a stable compound, wherein the substituents are selectedfrom the group consisting of —F, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH,—C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂,—C(NH)NH₂, —OR^(o), —SR^(o), —OC(O)R^(o), —OC(S)R^(o), —C(O)R^(o),—C(S)R^(o), —C(O)OR^(o), —C(S)OR^(o), —S(O)R^(o), —S(O)₂R^(o),—C(O)NHR^(o), —C(S)NHR^(o), —C(O)NR^(o)R^(o), —C(S)NR^(o)R^(o),—S(O)₂NHR^(o), —S(O)₂NR^(o)R^(o), —C(NH)NHR^(o), —C(NH)NR^(p)R^(c),—NHC(O)R^(o), —NHC(S)R^(o), —NR^(o)C(O)R^(o), —NR^(o)C(S)R^(o),—NHS(O)₂R^(o), —NR^(o)S(O)₂R^(o), —NHC(O)NHR^(o), —NHC(S)NHR^(o),—NR^(o)C(O)NH₂, —NR^(o)C(S)NH₂, —NR^(o)C(O)NHR^(o), —NR^(o)C(S)NHR^(o),—NHC(O)NR^(o)R^(o), —NHC(S)NR^(o)R^(o), —NR^(o)C(O)NR^(o)R^(o),—NR^(o)C(S)NR^(o)R^(o), —NHS(O)₂NHR^(o), —NR^(o)S(O)₂NH₂,—NR^(o)S(O)NHR^(o), —NHS(O)₂NR^(o)R^(o), —NR^(o)S(O)₂NR^(o)R^(o),—NHR^(o), —NR^(o)R^(o), —R^(e), —R^(f), and —R^(g). Furthermore,possible substitutions include subsets of these substitutions, such asare indicated herein, for example, in the description of compounds ofFormula III, attached at any available atom to produce a stablecompound. For example “fluoro substituted lower alkyl” denotes a loweralkyl group substituted with one or more fluoro atoms, such asperfluoroalkyl, where preferably the lower alkyl is substituted with 1,2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it isunderstood that substitutions are attached at any available atom toproduce a stable compound, when optionally substituted alkyl is an Rgroup of a moiety such as —OR (e.g. alkoxy), —SR (e.g. thioalkyl), —NHR(e.g. alkylamino), —C(O)NHR, and the like, substitution of the alkyl Rgroup is such that substitution of the alkyl carbon bound to any O, S,or N of the moiety (except where N is a heteroaryl ring atom) excludessubstituents that would result in any O, S, or N of the substituent(except where N is a heteroaryl ring atom) being bound to the alkylcarbon bound to any O, S, or N of the moiety. “C₂₋₆ alkyl” denotes loweralkyl containing 2-6 carbon atoms. A “substituted C₂₋₆ alkyl” denotesoptionally substituted lower alkyl containing 2-6 carbon atoms. A“substituted methyl” denotes methyl that is independently substituted,unless indicated otherwise, with 1, 2, or 3 substituents, wherein thesubstituents are selected as per optionally substituted lower alkyl.

“C₁₋₃ alkylene” refers to a divalent alkane-derived radical containing1-3 carbon atoms, straight chain or branched, from which two hydrogenatoms are taken from the same carbon atom or from different carbonatoms. C₁₋₃ alkylene includes methylene —CH₂—, ethylene —CH₂CH₂—,propylene —CH₂CH₂CH₂—, and isopropylene —CH(CH₃)CH₂— or —CH₂CH(CH₃)—.C₁₋₃ alkylene substituted with one or more substituents indicates C₁₋₃alkylene that is independently substituted, with one or more, preferably1, 2, 3, 4 or 5, also 1, 2, or 3 substituents as indicated, attached atany available atom to produce a stable compound.

“Lower alkenyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)and at least one, preferably 1-3, more preferably 1-2, most preferablyone, carbon to carbon double bond. Carbon to carbon double bonds may beeither contained within a straight chain or branched portion. Examplesof lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,and the like. A “substituted lower alkenyl” denotes lower alkenyl thatis independently substituted, unless indicated otherwise, with one ormore, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attachedat any available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of —F, —OH, —NH₂,—NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(o), —SR^(o), —OC(O)R^(o),—OC(S)R^(o), —C(O)R^(o), —C(S)R^(o), —C(O)OR^(o), —C(S)OR^(o),—S(O)R^(o), —S(O)₂R^(o), —C(O)NHR^(o), —C(S)NHR^(o), —C(O)NR^(o)R^(o),—C(S)NR^(o)R^(o), —S(O)₂NHR^(o), —S(O)₂NR^(o)R^(o), —C(NH)NHR^(o),—C(NH)NR^(p)R^(c), —NHC(O)R^(o), —NHC(S)R^(o), —NR^(o)C(O)R^(o),—NR^(o)C(S)R^(o), —NHS(O)₂R^(o), —NR^(o)S(O)₂R^(o), —NHC(O)NHR^(o),—NHC(S)NHR^(o), —NR^(o)C(O)NH₂, —NR^(o)C(S)NH₂, —NR^(o)C(O)NHR^(o),—NR^(o)C(S)NHR^(o), —NHC(O)NR^(o)R^(o), —NHC(S)NR^(o)R^(o),—NR^(o)C(O)NR^(o)R^(o), —NR^(o)C(S)NR^(o)R^(o), —NHS(O)₂NHR^(o),—NR^(o)S(O)₂NH₂, —NR^(o)S(O)₂NHR^(o), —NHS(O)₂NR^(o)R^(o),—NR^(o)S(O)₂NR^(o)R^(o), —NHR^(o), —NR^(o)R^(o), —R^(d), —R^(f), and—R^(g). Further, possible substitutions include subsets of thesesubstitutions, such as are indicated herein, for example, in thedescription of compounds of Formula III, attached at any available atomto produce a stable compound. For example “fluoro substituted loweralkenyl” denotes a lower alkenyl group substituted with one or morefluoro atoms, where preferably the lower alkenyl is substituted with 1,2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it isunderstood that substitutions are attached at any available atom toproduce a stable compound, substitution of alkenyl groups are such that—F, —C(O)—, —C(S)—, —C(NH)—, —S(O)—, —S(O)₂—, —O—, —S—, or N (exceptwhere N is a heteroaryl ring atom), are not bound to an alkene carbonthereof. Further, where alkenyl is a substituent of another moiety or anR group of a moiety such as —OR, —NHR, —C(O)R, and the like,substitution of the moiety is such that any —C(O)—, —C(S)—, —S(O)—,—S(O)₂—, —O—, —S—, or N thereof (except where N is a heteroaryl ringatom) are not bound to an alkene carbon of the alkenyl substituent or Rgroup. Further, where alkenyl is a substituent of another moiety or an Rgroup of a moiety such as —OR, —NHR, —C(O)NHR, and the like,substitution of the alkenyl R group is such that substitution of thealkenyl carbon bound to any O, S, or N of the moiety (except where N isa heteroaryl ring atom) excludes substituents that would result in anyO, S, or N of the substituent (except where N is a heteroaryl ring atom)being bound to the alkenyl carbon bound to any O, S, or N of the moiety.An “alkenyl carbon” refers to any carbon within an alkenyl group,whether saturated or part of the carbon to carbon double bond. An“alkene carbon” refers to a carbon within an alkenyl group that is partof a carbon to carbon double bond.

“Lower alkynyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)containing at least one, preferably one, carbon to carbon triple bond.Examples of alkynyl groups include ethynyl, propynyl, butynyl, and thelike. A “substituted lower alkynyl” denotes lower alkynyl that isindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of —F, —OH, —NH₂,—NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)NH₂, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(o), —SR^(o), —OC(O)R^(o),—OC(S)R^(o), —C(O)R^(o), —C(S)R^(o), —C(O)OR^(o), —C(S)OR^(o),—S(O)R^(o), —S(O)₂R^(o), —C(O)NHR^(o), —C(S)NHR^(o), —C(O)NR^(o)R^(o),—C(S)NR^(o)R^(o), —S(O)₂NHR^(o), —S(O)₂NR^(o)R^(o), —C(NH)NHR^(o),—C(NH)NR^(p)R^(c), —NHC(O)R^(o), —NHC(S)R^(o), —NR^(o)C(O)R^(o),—NR^(o)C(S)R^(o), —NHS(O)₂R^(o), —NR^(o)S(O)₂R^(o), —NHC(O)NHR^(o),—NHC(S)NHR^(o), —NR^(o)C(O)NH₂, —NR^(o)C(S)NH₂, —NR^(o)C(O)NHR^(o),—NR^(o)C(S)NHR^(o), —NHC(O)NR^(o)R^(o), —NHC(S)NR^(o)R^(o),—NR^(o)C(O)NR^(o)R^(o), —NR^(o)C(S)NR^(o)R^(o), —NHS(O)₂NHR^(o),—NR^(o)S(O)₂NH₂, —NR^(c)S(O)₂NHR^(o), —NHS(O)₂NR^(o)R^(o),—NR^(o)S(O)₂NR^(o)R^(o), —NHR^(o), —NR^(o)R^(o), —R^(d), —R^(e), and—R^(g). Further, possible substitutions include subsets of thesesubstitutions, such as are indicated herein, for example, in thedescription of compounds of Formula III, attached at any available atomto produce a stable compound. For example “fluoro substituted loweralkynyl” denotes a lower alkynyl group substituted with one or morefluoro atoms, where preferably the lower alkynyl is substituted with 1,2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it isunderstood that substitutions are attached at any available atom toproduce a stable compound, substitution of alkynyl groups are such that—F, —C(O)—, —C(S)—, —C(NH)—, —S(O)—, —S(O)₂—, —O—, —S—, or N (exceptwhere N is a heteroaryl ring atom) are not bound to an alkyne carbonthereof. Further, where alkynyl is a substituent of another moiety or anR group of a moiety such as —OR, —NHR, —C(O)R, and the like,substitution of the moiety is such that any —C(O)—, —C(S)—, —S(O)—,—S(O)₂—, —O—, —S—, or N thereof (except where N is a heteroaryl ringatom) are not bound to an alkyne carbon of the alkynyl substituent or Rgroup. Further, where alkynyl is a substituent of another moiety or an Rgroup of a moiety such as —OR, —NHR, —C(O)NHR, and the like,substitution of the alkynyl R group is such that substitution of thealkynyl carbon bound to any O, S, or N of the moiety (except where N isa heteroaryl ring atom) excludes substituents that would result in anyO, S, or N of the substituent (except where N is a heteroaryl ring atom)being bound to the alkynyl carbon bound to any O, S, or N of the moiety.An “alkynyl carbon” refers to any carbon within an alkynyl group,whether saturated or part of the carbon to carbon triple bond. An“alkyne carbon” refers to a carbon within an alkynyl group that is partof a carbon to carbon triple bond.

“Cycloalkyl” refers to saturated or unsaturated, non-aromaticmonocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8,more preferably 3-6, ring members per ring, such as cyclopropyl,cyclopentyl, cyclohexyl, adamantyl, and the like. A “substitutedcycloalkyl” is a cycloalkyl that is independently substituted, unlessindicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also1, 2, or 3 substituents, attached at any available atom to produce astable compound, wherein the substituents are selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,—C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂,—OR^(o), —SR^(o), —OC(O)R^(o), —OC(S)R^(o), —C(O)R^(o)o, —C(S)R^(o),—C(O)OR^(o), —C(S)OR^(o), —S(O)R^(o), —S(O)₂R^(o), —C(O)NHR^(o),—C(S)NHR^(o), —C(O)NR^(o)R^(o), —C(S)NR^(o)R^(o), —S(O)₂NHR^(o),—S(O)₂NR^(o)R^(o), —C(NH)NHR^(o), —C(NH)NR^(p)R^(c), —NHC(O)R^(o),—NHC(S)R^(o), —NR^(o)C(O)R^(o), —NR^(o)C(S)R^(o), —NHS(O)₂R^(o),—NR^(o)S(O)₂R^(o), —NHC(O)NHR^(o), —NHC(S)NHR^(o), —NR^(o)C(O)NH₂,—NR^(o)C(S)NH₂, —NR^(o)C(O)NHR^(o), —NR^(o)C(S)NHR^(o),—NHC(O)NR^(o)R^(o), —NHC(S)NR^(o)R^(o), —NR^(o)C(O)NR^(o)R^(o),—NR^(o)C(S)NR^(o)R^(o), —NHS(O)₂NHR^(o), —NR^(o)S(O)₂NH₂,—NR^(o)S(O)₂NHR^(o), —NHS(O)₂NR^(o)R^(o), —NR^(o)S(O)₂NR^(o)R^(o),—NHR^(o), —NR^(o)OR^(o), —R^(d), —R^(e), —R^(f), and —R^(g).

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbonatoms in the ring are replaced by heteroatoms of O, S or N, and areoptionally fused with benzo or heteroaryl of 5-6 ring members.Heterocycloalkyl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.Heterocycloalkyl is also intended to include compounds in which a ringcarbon may be oxo substituted, i.e. the ring carbon is a carbonyl group,such as lactones and lactams. The point of attachment of theheterocycloalkyl ring is at a carbon or nitrogen atom such that a stablering is retained. Examples of heterocycloalkyl groups include, but arenot limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl,piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl,and dihydroindolyl. A “substituted heterocycloalkyl” is aheterocycloalkyl that is independently substituted, unless indicatedotherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3substituents, attached at any available atom to produce a stablecompound, wherein the substituents are selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,—C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂,—OR^(o), —SR^(o), —OC(O)R^(o), —OC(S)R^(o), —C(O)R^(o), —C(S)R^(o),—C(O)OR^(o), —C(S)OR^(o), —S(O)R^(o), —S(O)₂R^(o), —C(O)NHR^(o),—C(S)NHR^(o), —C(O)NR^(o)R^(o), —C(S)NR^(o)R^(o), —S(O)₂NHR^(o),—S(O)₂NR^(o)R^(o), —C(NH)NHR^(o), —C(NH)NR^(p)R^(c), —NHC(O)R^(o),—NHC(S)R^(o), —NR^(o)C(O)R^(o), —NR^(o)C(S)R^(o), —NHS(O)₂R^(o),—NR^(o)S(O)₂R^(o), —NHC(O)NHR^(o), —NHC(S)NHR^(o), —NR^(o)C(O)NH₂,—NR^(o)C(S)NH₂, —NR^(o)C(O)NHR^(o), —NR^(o)C(S)NHR^(o),—NHC(O)NR^(o)R^(o), —NHC(S)NR^(o)R^(o), —NR^(o)C(O)NR^(o)R^(o),—NR^(o)C(S)NR^(o)R^(o), —NHS(O)₂NHR^(o), —NR^(o)S(O)₂NH₂,—NR^(o)S(O)₂NHR^(o), —NHS(O)₂NR^(o)R^(o), —NR^(o)S(O)₂NR^(o)R^(o),—NHR^(o), —NR^(o)R^(o), —R^(d), —R^(e), —R^(f), and —R^(g).

“Aryl” alone or in combination refers to a monocyclic or bicyclic ringsystem containing aromatic hydrocarbons such as phenyl or naphthyl,which may be optionally fused with a cycloalkyl of preferably 5-7, morepreferably 5-6, ring members. “Arylene” is a divalent aryl. A“substituted aryl” is an aryl that is independently substituted, unlessindicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also1, 2, or 3 substituents, attached at any available atom to produce astable compound, wherein the substituents are selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,—C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂,—OR^(o), —SR^(o), —OC(O)R^(o), —OC(S)R^(o), —C(O)R^(o), —C(S)R^(o),—C(O)OR^(o), —C(S)OR^(o), —S(O)R^(o), —S(O)₂R^(o), —C(O)NHR^(o),—C(S)NHR^(o), —C(O)NR^(o)R^(o), —C(S)NR^(o)R^(o), —S(O)₂NHR^(o),—S(O)₂NR^(o)R^(o), —C(NH)NHR^(o), —C(NH)NR^(p)R^(c), —NHC(O)R^(o),—NHC(S)R^(o), —NR^(o)C(O)R^(o), —NR^(o)C(S)R^(o), —NHS(O)₂R^(o),—NR^(o)S(O)₂R^(o), —NHC(O)NHR^(o), —NHC(S)NHR^(o), —NR^(o)C(O)NH₂,—NR^(o)C(S)NH₂. —NR^(c)C(O)NHR^(o), —NR^(o)C(S)NHR^(o),—NHC(O)NR^(o)R^(o), —NHC(S)NR^(o)R^(o), —NR^(o)(O)NR^(o)R^(o),—NR^(o)C(S)NR^(o)R^(o), —NHS(O)₂NHR^(o), —NR^(o)S(O)₂NH₂,—NR^(o)S(O)₂NHR^(o), —NHS(O)₂NR^(o)R^(o), —NR^(o)S(O)₂NR^(o)R^(o),—NHR^(o), —NR^(o)R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). A“substituted arylene” is a divalent substituted aryl.

“Heteroaryl” alone or in combination refers to a monocyclic aromaticring structure containing 5 or 6 ring atoms, or a bicyclic aromaticgroup having 8 to 10 atoms, containing one or more, preferably 1-4, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group consisting of O, S, and N. Heteroaryl is alsointended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is thepoint of attachment of the heteroaryl ring structure such that a stablecompound is produced. Examples of heteroaryl groups include, but are notlimited to, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl,benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl,pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl,isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl,triazolyl, furanyl, benzofuryl, and indolyl. “Nitrogen containingheteroaryl” refers to heteroaryl wherein any heteroatoms are N.“Heteroarylene” is a divalent heteroaryl. A “substituted heteroaryl” isa heteroaryl that is independently substituted, unless indicatedotherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3substituents, attached at any available atom to produce a stablecompound, wherein the substituents are selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,—C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂,—OR^(o), —SR^(o), —OC(O)R^(o), —OC(S)R^(o), —C(O)R^(o), —C(S)R^(o),—C(O)OR^(o), —C(S)OR^(o), —S(O)R^(o), —S(O)₂R^(o), —C(O)NHR^(o),—C(S)NHR^(o), —C(O)NR^(o)R^(o), —C(S)NR^(o)R^(o), —S(O)₂NHR^(o),—S(O)₂NR^(o)R^(o), —C(NH)NHR^(o), —C(NH)NR^(p)R^(c), —NHC(O)R^(o),—NHC(S)R^(o), —NR^(o)C(O)R^(o), —NR^(o)C(S)R^(o), —NHS(O)₂R^(o),—NR^(o)S(O)₂R^(o), —NHC(O)NHR^(o), —NHC(S)NHR^(o), —NR^(o)C(O)NH₂,—NR^(o)C(S)NH₂, —NR^(o)C(O)NHR^(o), —NR^(o)C(S)NHR^(o),—NHC(O)NR^(o)R^(o), —NHC(S)NR^(o)R^(o), —NR^(o)C(O)NR^(o)R^(o),—NR^(o)C(S)NR^(o)R^(o), —NHS(O)₂NHR^(o), —NR^(o)S(O)₂NH₂,—NR^(o)S(O)₂NHR^(o), —NHS(O)₂NR^(o)R^(o), —NR^(o)S(O)₂NR^(o)R^(o),—NHR^(o), —NR^(o)R^(o), —R^(d), —R^(e), —R^(f), and —R^(g). “Substitutedheteroarylene” is a divalent substituted heteroaryl.

The variables R^(o), R^(p), R^(c), R^(d), R^(e), R^(f) and R^(g) as usedin the description of optional substituents for alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl and heteroaryl are defined asfollows:

each R^(o), R^(p), and R^(c) are independently selected from the groupconsisting of R^(d), R^(e), R^(f), and R^(g), or R^(p) and R^(c) combinewith the nitrogen to which they are attached to form a 5-7 memberedheterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl,wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogencontaining heteroaryl are optionally substituted with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected fromthe group consisting of halogen, —NO₂, —CN, —OH, —NH₂, —OR^(u), —SR^(u),—NHR^(u), —NR^(u)R^(u), —R^(x), and —R^(y);each R^(d) is independently lower alkyl, wherein lower alkyl isoptionally substituted with one or more, preferably 1, 2, 3, 4 or 5,also 1, 2 or 3 substituents selected from the group consisting offluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k),—SR^(k), —OC(O)R^(k), —OC(S)R^(k), —C(O)R^(k), —C(S)R^(k), —C(O)OR^(k),—C(S)OR^(k), —S(O)R^(k), —S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k),—C(O)NR^(k)R^(k), —C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k),—C(NH)NHR^(k), —C(NH)NR^(m)R^(n), —NHC(O)R^(k), —NHC(S)R^(k),—NR^(k)C(O)R^(k), —NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k),—NHC(O)NHR^(k), —NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂,—NR^(k)C(O)NHR^(k), —NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k),—NHC(S)NR^(k)R^(k), —NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k),—NHS(O)₂NHR^(k), —NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k),—NHS(O)₂NR^(k)R^(k), —NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k),—R^(i), and —R^(j);each R^(e) is independently lower alkenyl, wherein lower alkenyl isoptionally substituted with one or more, preferably 1, 2, 3, 4 or 5,also 1, 2 or 3 substituents selected from the group consisting offluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₁₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k),—SR^(k), —OC(O)R^(k), —OC(S)R^(k), —C(O)R^(k), —C(S)R^(k), —C(O)OR^(k),—C(S)OR^(k), —S(O)R^(k), —S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k),—C(O)NR^(k)R^(k), —C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k),—C(NH)NHR^(k), —C(NH)NR^(m)R^(n), —NHC(O)R^(k), —NHC(S)R^(k),—NR^(k)C(O)R^(k), —NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k),—NHC(O)NHR^(k), —NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂,—NR^(k)C(O)NHR^(k), —NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k),—NHC(S)NR^(k)R^(k), —NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k),—NHS(O)₂NHR^(k), —NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k),—NHS(O)₂NR^(k)R^(k), —NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k),—R^(h), and —R^(j);each R^(f) is independently lower alkynyl, wherein lower alkynyl isoptionally substituted with one or more, preferably 1, 2, 3, 4 or 5,also 1, 2 or 3 substituents selected from the group consisting offluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k),—SR^(k), —OC(O)R^(k), —OC(S)R^(k), —C(O)R^(k), —C(S)R^(k), —C(O)OR^(k),—C(S)OR^(k), —S(O)R^(k), —S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k),—C(O)NR^(k)R^(k), —C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k),—C(NH)NHR^(k), —C(NH)NR^(m)R^(n), —NHC(O)R^(k), —NHC(S)R^(k),—NR^(k)C(O)R^(k), —NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k),—NHC(O)NHR^(k), —NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂,—NR^(k)C(O)NHR^(k), —NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k),—NHC(S)NR^(k)R^(k), —NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k),—NHS(O)₂NHR^(k), —NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k),—NHS(O)₂NR^(k)R^(k), —NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k),—R^(h), and —R^(j);each R^(g) is independently selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl, and heteroaryl are optionally substituted withone or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituentsselected from the group consisting of halogen, —OH, —NH₂, —NO₂, —CN,—C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k), —SR^(k), —OC(O)R^(k), —OC(S)R^(k),—C(O)R^(k), —C(S)R^(k), —C(O)OR^(k), —C(S)OR^(k), —S(O)R^(k),—S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k), —C(O)NR^(k)R^(k),—C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k), —C(NH)NHR^(k),—C(NH)NR^(k)R^(k), —NHC(O)R^(k), —NHC(S)R^(k), —NR^(k)C(O)R^(k),—NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k), —NHC(O)NHR^(k),—NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂, —NR^(k)C(O)NHR^(k),—NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k), —NHC(S)NR^(k)R^(k),—NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k), —NHS(O)₂NHR^(k),—NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k), —NHS(O)₂NR^(k)R^(k),—NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k), —R^(h), —R^(i), and—R^(j);

-   -   wherein R^(k), R^(m), and R^(n) at each occurrence are        independently selected from the group consisting of R^(h),        R^(i), and R^(j), or R^(m) and R^(n) combine with the nitrogen        to which they are attached form a 5-7 membered heterocycloalkyl        or a 5 or 7 membered nitrogen containing heteroaryl, wherein the        5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen        containing heteroaryl are optionally substituted with one or        more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents        selected from the group consisting of halogen, —NO₂, —CN, —OH,        —NH₂, OR^(u), —SR^(u), —NHR^(u), —NR^(u)R^(u), —R^(x), and        —R^(y);    -   wherein each R^(h) is independently lower alkyl optionally        substituted with one or more, preferably 1, 2, 3, 4 or 5, also        1, 2, or 3 substituents selected from the group consisting of        fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂,        —C(NH)NH₂, —OR^(r), —SR^(r), —OC(O)R^(r), —OC(S)R^(r),        —C(O)R^(r), —C(S)R^(r), —C(O)OR^(r), —C(S)OR^(r), —S(O)R^(r),        —S(O)₂R^(r), —C(O)NHR^(r), —C(S)NHR^(r), —C(O)NR^(r)R^(r),        —C(S)NR^(r)R^(r), —S(O)₂NHR^(r), —S(O)₂NR^(r)R^(r),        —C(NH)NHR^(r), —C(NH)NR^(s)R^(t), —NHC(O)R^(r), —NHC(S)R^(r),        —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r), —NHS(O)₂R^(r),        —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r), —NHC(S)NHR^(r),        —NR^(r)C(O)NH₁₂, —NR^(r)C(S)NH₂, —NR^(r)C(O)NHR^(r),        —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r), —NHC(S)NR^(r)R^(r),        —NR^(r)C(O)NR^(r)R^(r), —NR^(r)C(S)NR^(r)R^(r), —NHS(O)₂NHR^(r),        —NR^(r)S(O)₂NH₂, —NR^(r)S(O)₂NHR^(r), —NHS(O)₂NR^(r)R^(r),        —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), —NR^(r)R^(r), —R^(i), and        —R^(j);    -   wherein each R^(i) is independently selected from the group        consisting of lower alkenyl and lower alkynyl, wherein lower        alkenyl or lower alkynyl are optionally substituted with one or        more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents        selected from the group consisting of fluoro, —OH, —NH₂, —NO₂,        —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,        —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(r),        —SR^(r), —OC(O)R^(r), —OC(S)R^(r), —C(O)R^(r), —C(S)R^(r),        —C(O)OR^(r), —C(S)OR^(r), —S(O)R^(r), —S(O)₂R^(r), —C(O)NHR^(r),        —C(S)NHR^(r), —C(O)NR^(r)R^(r), —C(S)NR^(r)R^(r), —S(O)₂NHR^(r),        —S(O)₂NR^(r)R^(r), —C(NH)NHR^(r), —C(NH)NR^(r)R^(r),        —NHC(O)R^(r), —NHC(S)R^(r), —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r),        —NHS(O)₂R^(r), —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r),        —NHC(S)NHR^(r), —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂,        —NR^(r)C(O)NHR^(r), —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r),        —NHC(S)NR^(r)R^(r), —NR^(r)C(O)NR^(r), —NR^(r)C(S)NR^(r)R^(r),        —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂, —NR^(r)S(O)₂NHR^(r),        —NHS(O)₂NR^(r)R^(r), —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r),        —NR^(r)R^(r), and —R^(j);    -   wherein each R^(j) is independently selected from the group        consisting of cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl are optionally substituted with one or more,        preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected        from the group consisting of halogen, —OH, —NH₂, —NO₂, —CN,        —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₁₂, —S(O)₂NH₂, —NHC(O)NH₂,        —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(r), —SR^(r),        —OC(O)R^(r), —OC(S)R^(r), —C(O)R^(r), —C(S)R^(r), —C(O)OR^(r),        —C(S)OR^(r), —S(O)R^(r), —S(O)₂R^(r), —C(O)NHR^(r),        —C(S)NHR^(r), —C(O)NR^(r)R^(r), —C(S)NR^(r)R^(r), —S(O)₂NHR^(r),        —S(O)₂NR^(r)R^(r), —C(NH)NHR^(r), —C(NH)NR^(r)R^(r),        —NHC(O)R^(r), —NHC(S)R^(r), —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r),        —NHS(O)₂R^(r), —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r),        —NHC(S)NHR^(r), —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂,        —NR^(r)C(O)NHR^(r), —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r),        —NHC(S)NR^(r)R^(r), —NR^(r)C(O)NR^(r)R^(r),        —NR^(r)C(S)NR^(r)R^(r), —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂,        —NR^(r)S(O)₂NHR^(r), —NHS(O)₂NR^(r)R^(r),        —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), —NR^(r)R^(r),        cycloalkylamino, and —R^(x);        -   wherein each R^(r), R^(s), and R^(t) at each occurrence are            independently selected from the group consisting of lower            alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl            is optionally substituted with one or more, preferably 1, 2,            3, 4 or 5, also 1, 2, or 3 substituents selected from the            group consisting of —R^(y), fluoro, —OH, —NH₂, lower alkoxy,            fluoro substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkylamino, di-alkylamino,            and cycloalkylamino, provided, however, that any            substitution of the lower alkyl carbon bound to any O, S, or            N, of —OR^(r), —SR^(r), —C(O)OR^(r), —C(S)OR^(r),            —C(O)NHR^(r), —C(S)NHR^(r), —C(O)NR^(r)R^(r),            —C(S)NR^(r)R^(r), —S(O)₂NHR^(r), —S(O)₂NR^(r)R^(r),            —C(NH)NHR^(r), —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r),            —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r), —NHC(S)NHR^(r),            —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂, —NR^(r)C(O)NHR^(r),            —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r), —NHC(S)NR^(r)R^(r),            —NR^(r)C(O)NR^(r)R^(r), —NR^(r)C(S)NR^(r)R^(r),            —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂, —NR^(r)S(O)₂NHR^(r),            —NHS(O)₂NR^(r)R^(r), —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), or            —NR^(r)R^(r) is selected from the group consisting of fluoro            and —R^(y), and wherein C₃₋₆ alkenyl or C₃₋₆ alkanyl are            optionally substituted with one or more, preferably 1, 2, 3,            4 or 5, also 1, 2, or 3 substituents selected from the group            consisting of —R^(y), fluoro, lower alkyl, fluoro            substituted lower alkyl, lower alkoxy, fluoro substituted            lower alkoxy, lower alkylthio, fluoro substituted lower            alkylthio, mono-alkylamino, di-alkylamino, and            cycloalkylamino, provided, however, that any substitution of            the C₃₋₆alkenyl or C₃₋₆ alkynyl carbon bound to any O, S, or            N, of —OR^(r), —SR^(r), —C(O)OR^(r), —C(S)OR^(r),            —C(O)NHR^(r), —C(S)NHR^(r), —C(O)NR^(r)R^(r),            —C(S)NR^(r)R^(r), —S(O)₂NHR^(r), —S(O)₂NR^(r)R^(r),            —C(NH)NHR^(r), —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r),            —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r), —NHC(S)NHR^(r),            —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂, —NR^(r)C(O)NHR^(r),            —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r), —NHC(S)NR^(r)R^(r),            —NR^(r)C(O)NR^(r)R^(r), —NR C(S)NR^(r)R^(r),            —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂, —NR^(r)S(O)₂NHR^(r),            —NHS(O)₂NR^(r)R^(r), —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), or            —NR^(r)R^(r) is selected from the group consisting of            fluoro, lower alkyl, fluoro substituted lower alkyl, and            —R^(y), and wherein cycloalkyl, heterocycloalkyl, aryl, and            heteroaryl are optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of halogen, —OH, —NH₂,            —NO₂, —CN, lower alkyl, fluoro substituted lower alkyl,            lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino, or            R^(s) and R^(t) combine with the nitrogen to which they are            attached form a 5-7 membered heterocycloalkyl or a 5 or 7            membered nitrogen containing heteroaryl, wherein the 5-7            membered heterocycloalkyl or 5 or 7 membered nitrogen            containing heteroaryl are optionally substituted with one or            more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3            substituents selected from the group consisting of halogen,            —NO₂, —CN, —OH, —NH₂, OR^(u), —SR^(u), —NHR^(u),            —NR^(u)R^(u), —R^(x), and —R^(y);        -   wherein each R^(u) is independently selected from the group            consisting of lower alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl,            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein            lower alkyl is optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of —R^(y), fluoro, —OH,            —NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino,            provided, however, that any substitution of the lower alkyl            carbon bound to the O of —OR^(u), S of —SR^(u), or N of            —NHR^(u) is fluoro or —R^(y), and wherein C₃₋₆alkenyl or            C₃₋₆ alkynyl are optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of —R^(y), fluoro, —OH,            —NH₂, lower alkyl, fluoro substituted lower alkyl, lower            alkoxy, fluoro substituted lower alkoxy, lower alkylthio,            fluoro substituted lower alkylthio, mono-alkylamino,            di-alkylamino, and cycloalkylamino, provided, however, that            any substitution of the C₃₋₆ alkenyl or C₃₋₄ alkynyl carbon            bound to the O of —OR^(u), S of —SR^(u), or N of —NHR^(u) is            fluoro, lower alkyl, fluoro substituted lower alkyl, or            —R^(y), and wherein cycloalkyl, heterocycloalkyl, aryl, and            heteroaryl are optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of halogen, —OH, —NH₂,            —NO₂, —CN, lower alkyl, fluoro substituted lower alkyl,            lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino;        -   wherein each R^(x) is selected from the group consisting of            lower alkyl, lower alkenyl and lower alkynyl, wherein lower            alkyl is optionally substituted with one or more, preferably            1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from            the group consisting of —R^(y), fluoro, —OH, —NH₂, lower            alkoxy, fluoro substituted lower alkoxy, lower alkylthio,            fluoro substituted lower alkylthio, mono-alkylamino,            di-alkylamino, and cycloalkylamino, and wherein lower            alkenyl or lower alkynyl are optionally substituted with one            or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3            substituents selected from the group consisting of —R^(y),            fluoro, —OH, —NH₂, lower alkyl, fluoro substituted lower            alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino;        -   wherein each R^(y) is selected from the group consisting of            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are            optionally substituted with one or more, preferably 1, 2, 3,            4 or 5, also 1, 2, or 3 substituents selected from the group            consisting of halogen, —OH, —NH₂, —NO₂, —CN, lower alkyl,            fluoro substituted lower alkyl, lower alkoxy, fluoro            substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkylamino, di-alkylamino,            and cycloalkylamino.

In some embodiments, all occurrences of optionally substituted loweralkyl, optionally substituted C₂, alkyl, optionally substituted loweralkenyl, or optionally substituted lower alkynyl are optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of fluoro, —NO₂, —CN, —OR¹, —SR^(1a),—NR^(1a)R^(1a), —OC(O)R^(1a), —OC(S)R^(1a), —C(O)R^(1a), —C(S)R^(1a),—C(O)OR^(1a), —C(S)OR^(1a), —C(O)NR^(1a)R^(1a), —C(S)NR^(1a)R^(1a),—S(O)₂NR^(1a)R^(1a), —C(NH)NR^(1a)R^(1a), —NR^(1a)C(O)R^(1a),—NR^(1a)C(S)R^(1a), —NR^(1a)S(O)₂R^(1a), —NR^(1a)C(O)NR^(1a)R^(1a),—NR^(1a)C(S)NR^(1a)R^(1a), —NR^(1a)S(O)₂NR^(1a)R^(1a), S(O)R^(1a),—S(O)₂R^(1a), cycloalkyl, heterocycloalkyl, aryl and heteroaryl, whereincycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of halogen, —NO₂, —CN, —OR^(1a),—SR^(1a), —NR^(1a)R^(1a), —OC(O)R^(1a), —OC(S)R^(1a), —C(O)R^(1a),—C(S)R^(1a), —C(O)OR^(1a), —C(S)OR^(1a), —C(O)NR^(1a)R^(1a),—C(S)NR^(1a)R^(1a), —S(O)₂NR^(1a)R^(1a), —C(NH)NR^(1a)R^(1a),—NR^(1a)C(O)R^(1a), —NR^(1a)C(S)R^(1a), —NR^(1a)S(O)₂R^(1a),—NR^(1a)C(O)NR^(1a)R^(1a), —NR^(1a)C(S)NR^(1a)R^(1a),—NR^(1a)S(O)₂NR^(1a)R^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —R^(1b), andlower alkyl optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of fluoro,—OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and —R^(1b), and all occurrences of optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted 5-7 membered heterocycloalkyl, optionallysubstituted aryl, optionally substituted arylene, optionally substitutedheteroaryl, optionally substituted heteroarylene, or optionallysubstituted 5 or 7 membered nitrogen containing heteroaryl areoptionally substituted with one or more, also 1, 2, or 3 groups orsubstituents selected from the group consisting of halogen, —NO₂, —CN,—OR^(1a), —SR^(1a), —NR^(1a)R^(1a), —OC(O)R^(1a), —OC(S)R^(1a),—C(O)R^(1a), —C(S)R^(1a), —C(O)OR^(1a), —C(S)OR^(1a),—C(O)NR^(1a)R^(1a), —C(S)NR^(1a)R^(1a), —S(O)₂NR^(1a)R^(1a),—C(NH)NR^(1a)R^(1a), —NR^(1a)C(O)R^(1a), —NR^(1a)C(S)R^(1a),—NR^(1a)S(O)₂R^(1a), —NR^(1a)C(O)NR^(1a)R^(1a),—NR^(1a)C(S)NR^(1a)R^(1a), —NR^(1a)S(O)₂NR^(1a)R^(1a), —S(O)R^(1a),—S(O)₂R^(1a), —R^(1b), and lower alkyl optionally substituted with oneor more, also 1, 2 or 3 groups or substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino, and —R^(1b), wherein R^(1a) is selectedfrom the group consisting of hydrogen, provided, however, that hydrogenis not bound to any of C(S), C(O), S(O), or S(O)₂ of —OC(O)R^(1a),—OC(S)R^(1a), —C(O)R^(1a), —C(S)R^(a), —NR^(1a)C(O)R^(1a),—NR^(1a)C(S)R^(1a), —NR^(1a)S(O)₂R^(1a), —S(O)R^(1a), or —S(O)₂R^(1a),—R^(1b), and lower alkyl optionally substituted with one or more, also1, 2 or 3 groups or substituents selected from the group consisting offluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and —R^(1b), provided, however, that any substitution ofthe alkyl carbon bound to O, S, or N of —OR^(1a), —SR^(1a),—NR^(1a)R^(1a), —C(O)OR^(1a), —C(S)OR^(1a), —C(O)NR^(1a)R^(1a),—C(S)NR^(1a)R^(1a), —S(O)₂NR^(1a)R^(1a), —C(NH)NR^(1a)R^(1a),—NR^(1a)C(O)R^(1a), —NR^(1a)C(S)R^(1a), —NR^(1a)S(O)₂R^(1a),—NR^(1a)C(O)NR^(1a)R^(1a), —NR^(1a)C(S)NR^(1a)R^(1a), or—NR^(1a)S(O)₂NR^(1a)R^(1a), is fluoro or —R^(1b), and wherein —R^(1b) isselected from the group consisting of cycloalkyl, heterocycloalkyl, aryland heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl andheteroaryl are optionally substituted with one or more, also 1, 2 or 3groups or substituents selected from the group consisting of halogen,—CN, —H, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and cycloalkylamino.

In some embodiments, all occurrences of optionally substituted loweralkyl, optionally substituted C₂₋₆ alkyl, optionally substituted loweralkenyl, or optionally substituted lower alkynyl are optionallysubstituted with one or more, also 1, 2 or 3 groups or substituentsselected from the group consisting of fluoro, —CN, —OR^(1a), —SR^(1a),—NR^(1a)R^(1a), —C(O)R^(1a), —C(S)R^(1a), —C(O)OR^(1a),—C(O)NR^(1a)R^(1a), —C(S)NR^(1a)R^(1a), —S(O)₂NR^(a)R^(1a),—NR^(1a)C(O)R^(1a), —NR^(1a)C(S)R^(1a), —NR^(1a)S(O)₂R^(1a),—S(O)R^(1a), —S(O)₂R^(1a), cycloalkyl, heterocycloalkyl, aryl andheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroarylare optionally substituted with one or more, also 1, 2 or 3 groups orsubstituents selected from the group consisting of halogen, —CN,—OR^(1a), —SR^(1a), —NR^(1a)R^(1a), —C(O)R^(1a), —C(S)R^(1a),—C(O)OR^(1a), —C(O)NR^(1a)R^(1a), —C(S)NR^(1a)R^(1a),—S(O)₂NR^(1a)R^(1a), —NR^(1a)C(O)R^(1a), —NR^(1a)C(S)R^(1a),—NR^(1a)S(O)₂R^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —R^(1b), and lower alkyloptionally substituted with one or more, also 1, 2 or 3 groups orsubstituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, and—R^(1b), and all occurrences of optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted 5-7membered heterocycloalkyl, optionally substituted aryl, optionallysubstituted arylene, optionally substituted heteroaryl, optionallysubstituted heteroarylene, or optionally substituted 5 or 7 memberednitrogen containing heteroaryl are optionally substituted with one ormore, also 1,2, or 3 groups or substituents selected from the groupconsisting of halogen, —CN, —OR^(1a), —SR^(1a), —NR^(1a)R^(1a),—C(O)R^(1a), —C(S)R^(1a), —C(O)OR^(1a), —C(O)NR^(1a)R^(1a),—C(S)NR^(1a)R^(1a), —S(O)₂NR^(1a)R^(1a), —NR^(1a)C(O)R^(1a),—NR^(1a)C(S)R^(1a), —NR^(1a)S(O)₂R^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—R^(1b), and lower alkyl optionally substituted with one or more, also1, 2 or 3 groups or substituents selected from the group consisting offluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower alkoxy, loweralkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and —R^(1b), wherein R^(1a) is selected from the groupconsisting of hydrogen, provided, however, that hydrogen is not bound toany of C(S), C(O), S(O), or S(O)₂ of —C(O)R^(1a), —C(S)R^(1a),—NR^(1a)C(O)R^(1a), —NR^(1a)C(S)R^(1a), —NR^(1a)S(O)₂R^(1a), —S(O)R^(a),or —S(O)₂R^(1a), —R^(1a), and lower alkyl optionally substituted withone or more, also 1, 2 or 3 groups or substituents selected from thegroup consisting of fluoro, —OH, —NH₂, lower alkoxy, fluoro substitutedlower alkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino, and —R^(1b), provided, however, that anysubstitution of the alkyl carbon bound to O, S, or N of —OR^(1a),—SR^(1a), —NR^(1a)R^(1a), —C(O)OR^(1a), —C(O)NR^(1a)R^(1a),—C(S)NR^(a1)R^(1a), —S(O)₂NR^(1a)R^(1a), —NR^(1a)C(O)R^(1a),—NR^(1a)C(S)R^(1a), or —NR^(1a)S(O)₂R^(1a), is fluoro or —R^(1b), andwherein —R^(1b) is selected from the group consisting of cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more, also 1, 2 or 3 groups or substituents selected from thegroup consisting of halogen, —CN, —OH, —NH₂, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, fluoro substituted loweralkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

“Lower alkoxy” denotes the group —OR^(z), where R^(z) is lower alkyl.“Substituted lower alkoxy” denotes lower alkoxy in which R is loweralkyl substituted with one or more substituents as indicated herein, forexample, in the description of compounds of Formula III, includingdescriptions of substituted cycloalkyl, cycloheteroalkyl, aryl andheteroaryl, attached at any available atom to produce a stable compound.Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5substituents, also 1, 2, or 3 substituents. For example “fluorosubstituted lower alkoxy” denotes lower alkoxy in which the lower alkylis substituted with one or more fluoro atoms, where preferably the loweralkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3fluoro atoms. While it is understood that substitutions on alkoxy areattached at any available atom to produce a stable compound,substitution of alkoxy is such that O, S, or N (except where N is aheteroaryl ring atom), are not bound to the alkyl carbon bound to thealkoxy O. Further, where alkoxy is described as a substituent of anothermoiety, the alkoxy oxygen is not bound to a carbon atom that is bound toan O, S, or N of the other moiety (except where N is a heteroaryl ringatom), or to an alkene or alkyne carbon of the other moiety.

“Lower alkylthio” denotes the group —SR^(aa), where R^(aa) is loweralkyl. “Substituted lower alkylthio” denotes lower alkylthio in whichR^(aa) is lower alkyl substituted with one or more substituents asindicated herein, for example, in the description of compounds ofFormula III, including descriptions of substituted cycloalkyl,cycloheteroalkyl, aryl and heteroaryl, attached at any available atom toproduce a stable compound. Preferably, substitution of lower alkylthiois with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. Forexample “fluoro substituted lower alkylthio” denotes lower alkylthio inwhich the lower alkyl is substituted with one or more fluoro atoms,where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood thatsubstitutions on alkylthio are attached at any available atom to producea stable compound, substitution of alkylthio is such that O, S, or N(except where N is a heteroaryl ring atom), are not bound to the alkylcarbon bound to the alkylthio S. Further, where alkylthio is describedas a substituent of another moiety, the alkylthio sulfur is not bound toa carbon atom that is bound to an O, S, or N of the other moiety (exceptwhere N is a heteroaryl ring atom), or to an alkene or alkyne carbon ofthe other moiety.

“Amino” or “amine” denotes the group —NH₂. “Mono-alkylamino” denotes thegroup —NHR^(bb) where R^(bb) is lower alkyl. “Di-alkylamino” denotes thegroup —NR^(bb)R^(cc), where R^(bb) and R^(cc) are independently loweralkyl. “Cycloalkylamino” denotes the group —NR^(dd)R^(ee), where R^(dd)and R^(ee) combine with the nitrogen to form a 5-7 memberedheterocycloalkyl, where the heterocycloalkyl may contain an additionalheteroatom within the ring, such as O, N, or S, and may also be furthersubstituted with lower alkyl. Examples of 5-7 membered heterocycloalkylinclude, but are not limited to, piperidine, piperazine,4-methylpiperazine, morpholine, and thiomorpholine. While it isunderstood that when mono-alkylamino, di-alkylamino, or cycloalkylaminoare substituents on other moieties that are attached at any availableatom to produce a stable compound, the nitrogen of mono-alkylamino,di-alkylamino, or cycloalkylamino as substituents is not bound to acarbon atom that is bound to an O, S, or N of the other moiety.

A “nitrogen protecting group” is a chemical group covalently bound to anitrogen atom of a compound that is used to protect the nitrogen fromreaction during a synthetic step. The nitrogen protecting group may beadded to a compound and removed in a subsequent step by methods known tothose of skill in the art. Nitrogen protecting groups include, withoutlimitation, carbamates, amides, N-sulfonyl derivatives, groups offormula —C(O)OR, wherein R is, for example, methyl, ethyl, t-butyl,benzyl, phenylethyl, C_(H)═CHCH₂—, and the like, groups of the formula—C(O)R′, wherein R′ is, for example, methyl, phenyl, trifluoromethyl,and the like, groups of the formula —SO₂R″, wherein R″ is, for example,tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like. Other suitable nitrogen protectinggroups may be found in texts such as T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, the term “composition” refers to a formulation suitablefor administration to an intended animal subject for therapeuticpurposes that contains at least one pharmaceutically active compound andat least one pharmaceutically acceptable carrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectibles.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

As used herein, the terms “ligand” and “modulator” are used equivalentlyto refer to a compound that changes (i.e., increases or decreases) theactivity of a target biomolecule, e.g., an enzyme such as a kinase.Generally a ligand or modulator will be a small molecule, where “smallmolecule refers to a compound with a molecular weight of 1500 daltons orless, or preferably 1000 daltons or less, 800 daltons or less, or 600daltons or less. Thus, an “improved ligand” is one that possesses betterpharmacological and/or pharmacokinetic properties than a referencecompound, where “better” can be defined by one skilled in the relevantart for a particular biological system or therapeutic use.

In the context of binding compounds and ligands, the term “derivative”or “derivative compound” refers to a compound having a chemicalstructure that contains a common core chemical structure as a parent orreference compound, but differs by having at least one structuraldifference. e.g., by having one or more substituents added and/orremoved and/or replaced, and/or by having one or more atoms replacedwith different atoms. Unless clearly indicated to the contrary, the term“derivative” does not mean that the derivative is synthesized using theparent compound as a starting material or as an intermediate, althoughin some cases, the derivative may be synthesized from the parent.

Thus, the term “parent compound” refers to a reference compound havingstructural features also found in the derivative compound. Often but notalways, a parent compound has a simpler chemical structure than thederivative.

By “chemical structure” or “chemical substructure” is meant anydefinable atom or group of atoms that constitute an individuallyidentifiable portion of a molecule, such as a substituent moiety, a corewhich is optionally substituted, and the like. Normally, chemicalsubstructures of a ligand can have a role in binding of the ligand to atarget molecule, or can influence the three-dimensional shape,electrostatic charge, and/or conformational properties of the ligand.

The term “binds” in connection with the interaction between a target anda potential binding compound indicates that the potential bindingcompound associates with the target to a statistically significantdegree as compared to association with proteins generally (i.e.,non-specific binding). Thus, the term “binding compound” refers to acompound that has a statistically significant association with a targetmolecule. Preferably a binding compound interacts with a specifiedtarget with a dissociation constant (K_(D)) of 1 mM or less, 1 μM orless, 100 nM or less, 10 nM or less, or 1 nM or less.

In the context of compounds binding to a target, the terms “greateraffinity” and “selective” indicates that the compound binds more tightlythan a reference compound, or than the same compound in a referencecondition, i.e., with a lower dissociation constant. In someembodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50,100, 200, 400, 500, 1000, or 10,000-fold greater affinity.

As used herein in connection with compounds of the invention, the term“synthesizing” and like terms means chemical synthesis from one or moreprecursor materials. Further, by “assaying” is meant the creation ofexperimental conditions and the gathering of data regarding a particularresult of the experimental conditions. For example, enzymes can beassayed based on their ability to act upon a detectable substrate. Acompound or ligand can be assayed based on its ability to bind to aparticular target molecule or molecules.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with a particular biomolecule such as a protein kinase. Forexample, an agonist or antagonist of a particular biomolecule modulatesthe activity of that biomolecule, e.g., an enzyme, by either increasing(e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor)the activity of the biomolecule, such as an enzyme. Such activity istypically indicated in terms of an inhibitory concentration (IC₅₀) orexcitation concentration (EC₅₀) of the compound for an inhibitor oractivator, respectively, with respect to, for example, an enzyme.

In the context of the use, testing, or screening of compounds that areor may be modulators, the term “contacting” means that the compound(s)are caused to be in sufficient proximity to a particular molecule,complex, cell, tissue, organism, or other specified material thatpotential binding interactions and/or chemical reaction between thecompound and other specified material can occur.

As used herein in connection with amino acid or nucleic acid sequence,the term “isolate” indicates that the sequence is separated from atleast a portion of the amino acid and/or nucleic acid sequences withwhich it would normally be associated.

In connection with amino acid or nucleic sequences, the term “purified”indicates that the subject molecule constitutes a significantly greaterproportion of the biomolecules in a composition than the proportionobserved in a prior composition, e.g., in a cell culture. The greaterproportion can be 2-fold, 5-fold, 10-fold, or more than 10-fold, withrespect to the proportion found in the prior composition.

I. General

The present invention concerns compounds of Formula I and allsub-generic formulae, compounds of Formula II and all sub-genericformulae, and compounds of Formula III and all sub-generic formulae thatare modulators of protein kinases, for example without limitation, thecompounds are modulators of at least one of the kinases selected fromthe group consisting of Abl, Akt1, Akt2, Akt3, ALK, Alk5, B-Raf, Brk,Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2,EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4,Fms, Frk, Fyn, Gsk3α, Gsk3β, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKKbeta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, Kdr, Kit, LCK,MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB,PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2,Ret, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, Yes, and Zap70,and the use of such compounds in the treatment of diseases orconditions.

II. Kinase Targets and Indications of the Invention

Protein kinases play key roles in propagating biochemical signals indiverse biological pathways. More than 500 kinases have been described,and specific kinases have been implicated in a wide range of diseases orconditions (i.e., indications), including for example withoutlimitation, cancer, cardiovascular disease, inflammatory disease,neurological disease, and other diseases. As such, kinases representimportant control points for small molecule therapeutic intervention.Description of specific target protein kinases contemplated by thepresent invention follow:

Abl: Target Abl (i.e., Abelson Murine Leukemia Viral Oncogene Homolog 1)is a 122.9 kDa tyrosine kinase encoded by chromosome 9q34.1 (symbol:ABL1.) The mature protein comprises SH3 (i.e., Src homology region 3)and SH2 (i.e., Src homology region 2) domains and the TK (i.e., tyrosinekinase) domain.

OMIM indicates Abl is expressed ubiquitously and can be localized to thenucleus where it hinds DNA. Accordingly, Abl has been implicated inprocesses of cell differentiation, cell division, cell adhesion, andstress response. Alterations of the gene ABL1 by a t(9; 22) (q34; q11)chromosomal rearrangement or viral transduction lead to malignanttransformation, as in chronic myeloid leukemia (CML). The kinaseactivity of Abl is negatively regulated by the constituent SH3 domain,and deletion of the SH3 domain turns ABL1 into an oncogene. The t(9; 22)translocation occurs in greater than 90% of chronic myelogenousleukemia, 25 to 30% of adult and 2 to 10% of childhood acutelymphoblastic leukemia (ALL), and rare cases of acute myelogenousleukemia. The translocation results in the head-to-tail fusion of theBCR and ABL genes (Chissoe et al., Genomics 1995, 27: 67-82). TheDNA-binding activity of Abl is regulated by CDC2-mediatedphosphorylation suggesting a cell cycle function for ABL. Welch & Wang(Cell 1993, 75: 779-790) showed that the tyrosine kinase activity ofnuclear Abl is regulated in the cell cycle through a specificinteraction with the retinoblastoma protein RB1. A domain in theC-terminus of RB1 binds to the ATP-binding lobe of Abl, resulting inkinase inhibition. The RB-ABL interaction is not affected by the viraloncoproteins that bind to RB. Hyperphosphorylation of RB correlates withrelease of Abl and activation of Abl in S phase cells. In the nucleusAbl can enhance transcription, and this activity is inhibited by RB.Thus, nuclear Abl is an S phase-activated tyrosine kinase that mightparticipate directly in the regulation of transcription. (OnlineMendelian Inheritance in Man, OMIM (TM). Johns Hopkins University,Baltimore, Md. MIM Number: 189980: Dec. 20, 2005. World Wide Web URL:http://www3.ncbi.nlm.nih.gov/omim). Abl inhibitors may be useful intreating leukemia, including chronic myelogenous leukemia, acutelymphoblastic leukemia, and acute myelogenous leukemia.

Akt1: Target kinase Akt1 (i.e., v-akt murine thymoma viral oncogenehomolog 1) is a 55.7 kDa STK encoded by chromosome 14q32.32 (symbol:AKT1). Akt1 is also known as protein kinase B-alpha, or PKB-alpha. OMIMindicates phosphoinositide 3-kinases (i.e., PI3Ks) generate specificinositol lipids implicated in the regulation of cell growth,proliferation, survival, differentiation, and cytoskeletal changes. Oneof the best characterized targets of PI3K lipid products is the proteinkinase AKT, or protein kinase B (PKB). In quiescent cells, PKB residesin the cytosol in a low-activity conformation. Upon cellularstimulation, PKB is activated through recruitment to cellular membranesby PI3K lipid products and by phosphorylation by 3-primephosphoinositide-dependent kinase-1. Most proliferating cells areprogrammed to undergo apoptosis unless specific survival signals areprovided. PDGF promotes cellular proliferation, inhibits apoptosis, andactivates the RAS/PIK3/AKT1/IKBKA/NFKB1 pathway (Romashkova and Makarov,Nature 1999, 401: 86-90). In this pathway, NFKB1 does not induce c-mycand apoptosis, but instead induces putative antiapoptotic genes. Inresponse to PDGF, Akt1 transiently associates with IKBK and induces IKBKactivation (OMIM MIM Number: 164730: Oct. 26, 2005) Aberrant Akt1activity is correlated with) including gastric and prostate tumors,colorectal, ovarian, pancreatic, and breast cancer, glioblastoma andleukemia. Sun et al., Am J Pathol 2001, 159(2):431-7, report thatsignificantly increased AKT1 kinase activity was detected in primarycarcinomas of prostate (16 of 30), breast (19 of 50), and ovary (11 of28). Tanno et al., Cancer Res 2001, 61(2):589-93, provide evidence for alink between AKT signaling and the regulation of IGF-IR expression anddemonstrate that active AKT promotes the invasiveness of pancreaticcancer cells through the up-regulation of IGF-IR expression. Neri etal., Mol Cancer Res 2003, 1(3):234-46, suggest that an up-regulation ofthe PL3K/AKT1 pathway might be one of the survival mechanismsresponsible for the onset of resistance to chemotherapeutic anddifferentiating therapy in patients with acute leukemia. Akt1 activityis also important in schizophrenia and bipolar disorders. Emamian etal., Nat Genet. 2004, 36(2): 115-6, present convergent evidence for adecrease in AKT1 protein levels and levels of phosphorylation ofGSK3beta at Scr9 in the peripheral lymphocytes and brains of individualswith schizophrenia; a significant association between schizophrenia andan AKT1 haplotype associated with lower AKT1 protein levels; and agreater sensitivity to the sensorimotor gating-disruptive effect ofamphetamine, conferred by AKT1 deficiency. Akt1 inhibitors may be usefulin treating cancer, including gastric, prostate, colorectal, ovarian,pancreatic and breast cancer, glioblastoma and leukemia, and also foruse in combination with other chemotherapeutic drugs.

Akt2: Target kinase Akt2 (i.e., v-akt murine thymoma viral oncogenehomolog 2) is a 55.8 kDa STK encoded by chromosome 19q13.1-13.2 (symbol:AKT2). Akt2 is also known as protein kinase B beta, PKB-beta. OMIMindicates that the Akt2 isoform of Akt (see e.g., Akt1 and Akt3) isenriched in insulin-responsive tissues and has been implicated in themetabolic actions of insulin. Glucose homeostasis depends on insulinresponsiveness in target tissues, most importantly, muscle and liver.The critical initial steps in insulin action include phosphorylation ofscaffolding proteins and activation of phosphatidylinositol 3-kinase.These early events lead to activation of the serine-threonine proteinkinase Akt, also known as protein kinase B. Cho et al., Science 2001,292:1728-1731, showed that mice deficient in Akt2 are impaired in theability of insulin to lower blood glucose because of defects in theaction of the hormone on liver and skeletal muscle. Ablation of Akt2 inmice results in a mild but statistically significant fastinghyperglycemia due to peripheral insulin resistance and nonsuppressiblehepatic glucose production accompanied by inadequate compensatoryhyperinsulinemia (OMIM MIM Number: 164731: Oct. 26, 2005). Arboleda etal., Cancer Res 2003, 63(1):196-206 showed that AKT2 transfected breastand ovarian cancer cells demonstrated increased adhesion and invasionthrough collagen IV because of up-regulation of beta1 integrins and thatAKT2 cells were more metastatic than control cells in vivo. Yamamoto etal., Clin Cancer Res 2004, 10(8):2846-50 studied the prognosticsignificance of Akt2 and activated Akt expression in pancreatic ductaladenocarcinoma (PDAC), concluding that p-Akt expression is a significantprognostic indicator for PDAC and inhibition of Akt is a possiblemolecular approach for treatment of PDAC. Yuan et al., Oncogene 2000,19(19):2324-30, demonstrate that activation of AKT2 is a commonoccurrence in human ovarian cancer and that the PI 3-kinase/Akt pathwaymay be an important target for ovarian cancer intervention. Yuan et al.,J Biol Chem 2003, 278(26):23432-40, demonstrate that constitutivelyactive AKT2 renders cisplatin-sensitive A2780S ovarian cancer cellsresistant to cisplatin, whereas phosphatidylinositol 3-kinase inhibitoror dominant negative AKT2 sensitizes A2780S and cisplatin-resistantA2780CP cells to cisplatin-induced apoptosis through regulation of theASK1/JNK/p38 pathway. Akt2 inhibitors may be useful in treating cancer,including ovarian and pancreatic cancers, pancreatic ductaladenocarcinoma, and metastases of breast and ovarian cancer, and alsofor use in combination with other chemotherapeutic drugs, where such usesensitizes the tumor cells to the effects of the otherchemotherapeutics.

Akt3: Target kinase Akt3 (i.e., v-akt murine thymoma viral oncogenehomolog 3) is a 55.8 kDa STK encoded by chromosome 1q43-q44(symbol:AKT3); Akt3 is also known as PKB gamma. Akt3 was identified as aprotein kinase with high homology with the protein kinases A and C,hence, the name PKB. Akt3 comprises a PH domain that preferentiallybinds PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ over other phosphatidylinositols (PIs). In quiescent cells, PKB resides in the cytosol in alow-activity conformation.

Upon cellular stimulation, PKB is activated through recruitment tocellular membranes by PI3K lipid products and phosphorylation by3′-phosphoinositide-dependent kinase-1 (PDK1). Active PKB then appearsto detach from the plasma membrane and to translocate through thecytosol to the nucleus.

Stahl et al. have found that selective activation of the Akt3 proteinpromotes cell survival and tumor development in 43 to 60% of nonfamilialmelanomas. The predominant Akt isoform active in melanomas wasidentified by showing that small interfering RNA (siRNA) against onlyAkt3, and not Akt1 or Akt2, lowered the amount of phosphorylated(active) Akt in melanoma cells. The amount of active Akt3 increasedprogressively during melanoma tumor progression with highest levelspresent in advanced-stage metastatic melanomas. Mechanisms of Akt3deregulation occurred through a combination of overexpression of Akt3accompanying copy number increases of the gene and decreased PTENprotein function occurring through loss or haploinsufficiency of thePTEN gene. Targeted reduction of Akt3 activity with siRNA or byexpressing active PTEN protein stimulated apoptotic signaling, whichreduced cell survival by increasing apoptosis rates thereby inhibitingmelanoma tumor development. Therefore, Akt3 is a selective target inmelanoma cells which provides therapeutic opportunities for subjects inadvanced stages of the disease (Stahl et al., Cancer Res. 2004,64:7002-10). Nakatani et al., J Biol Chem 1999, 274(31):21528-32 showedthat in estrogen receptor-deficient breast cancer cells andandrogen-insensitive prostate cells, the amount of Akt3 enzymaticactivity was approximately 20-60-fold higher than in cells that wereestrogen- or androgen-responsive. These and other results indicate thatAkt3 may contribute to the more aggressive clinical phenotype of theestrogen receptor-negative breast cancers and androgen-insensitiveprostate carcinomas and inhibitors may provide therapeutic benefits intreating these cancers. Akt3 inhibitors may be useful in treatingcancer, including estrogen receptor-negative breast cancers,androgen-insensitive prostate carcinomas, and melanomas.

ALK: Target kinase ALK (i.e., anaplastic lymphoma kinase) is a 176.4 kDareceptor tyrosine kinase encoded by chromosome 2p23 (symbol: ALK). ALKappears to play a role in the development of the central nervous system.Perkins, et al., show that systemic ALCL is highly associated withanaplastic lymphoma kinase (ALK) gene translocations withover-expression of ALK protein. Anaplastic large cell lymphoma (ALCL)comprises 10-15% of childhood non-Hodgkin lymphomas (NHL) (Perkins etal., Br J Haematol 2005, 131(5):624-7). Marzec et al., states aberrantexpression of the ALK tyrosine kinase as a chimeric protein withnucleophosmin (NPM) and other partners plays a key role in malignantcell transformation of T-lymphocytes and other cells. Further, studieswith inhibitors of NPM/ALK enzyme activity suggest ALK as an attractivetherapeutic target in T-cell lymphomas and other malignancies thatexpress the kinase in an active form (Marzec et al., Lab Invest 2005,85(12):1544-54). ALK inhibitors may be useful in treating cancer,including anaplastic large cell lymphoma and other T cell lymphomas.

Alk5: Target kinase Alk5 (i.e., Activin receptor-like kinase 5) is a56.0 kDa STK encoded by chromosome 9q22 (symbol: TGFBR1). Alk5, the genefor which was isolated by Franzen et al (Cell 1993, 75: 681-692), isalso known as transforming growth factor-beta receptor, type I, fromwhich term the gene symbol derives. Among other activities, Alk5mediates the induction of multiple genes involved in cell-matrixinteractions. Alk5 inhibitors may be useful in treating pancreatic andbiliary cancers and cutaneous T-cell lymphoma.

B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogenehomolog B1) is a 84.4 kDa serine/threonine kinase encoded by chromosome7q34 (symbol: BRAF). The mature protein comprises RBD (i.e., Ras bindingdomain), C1 (i.e., protein kinase C conserved region 1) and STK (i.e.,serine/threonine kinase) domains.

Target kinase B-Raf is involved in the transduction of mitogenic signalsfrom the cell membrane to the nucleus and may play a role in thepostsynaptic responses of hippocampal neurons. As such, genes of the RAFfamily encode kinases that are regulated by Ras and mediate cellularresponses to growth signals. Indeed, B-Raf kinase is a key component ofthe RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays afundamental role in the regulation of cell growth, division andproliferation, and, when constitutively activated, causes tumorigenesis.Among several isoforms of Raf kinase, the B-type, or B-Raf, is thestrongest activator of the downstream MAP kinase signaling.

The BRAF gene is frequently mutated in a variety of human tumors,especially in malignant melanoma and colon carcinoma. The most commonreported mutation was a missense thymine (T) to adenine (A) transversionat nucleotide 1796 (T1796A; amino acid change in the B-Raf protein isVal<600> to Glu<600>) observed in 80% of malignant melanoma tumors.Functional analysis reveals that this transversion is the only detectedmutation that causes constitutive activation of B-Raf kinase activity,independent of RAS activation, by converting B-Raf into a dominanttransforming protein.

Niihori et al., report that in 43 individuals withcardio-facio-cutaneous (CFC) syndrome, they identified two heterozygousKRAS mutations in three individuals and eight BRAF mutations in 16individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway isa common molecular basis for the three related disorders (Niihori etal., Nat. Genet. 2006, 38(3):294-6).

B-Raf inhibitors may be useful in treating neurologic diseases such asischemic stroke, multi-infarct dementia, head injury, spinal cordinjury, Alzheimer's disease (AD), Parkinson's disease; neoplasticdiseases including, but not limited to, melanoma, glioma, sarcoma,carcinoma (e.g. lung, breast, pancreatic, renal), lymphoma (e.g.histiocytic lymphoma) and cancer of the thyroid, lung (e.g. small celllung cancer), liver, breast, ovary and colon, neurofibromatosis,myelodysplastic syndrome, leukemia, tumor angiogenesis; pain ofneuropathic or inflammatory origin, including acute pain, chronic pain,and migraine; cardiovascular diseases including heart failure, cardiachypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes),atherosclerosis, reperfusion injury; inflammation including, but notlimited to, psoriasis, polycystic kidney disease (PKD), arthritis andautoimmune diseases and conditions, osteoarthritis, endometriosis,scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis,inflammatory bowel disease (IBD); immunodeficiency diseases, organtransplant rejection, graft versus host disease; renal or prostaticdiseases including diabetic nephropathy, nephrosclerosis,glomerulonephritis, prostate hyperplasia; metabolic disorders, obesity;infection, including, but not limited to Helicobacter pylori andInfluenza virus, fever, sepsis; pulmonary diseases including chronicobstructive pulmonary disease (COPD) and acute respiratory distresssyndrome (ARDS); genetic developmental diseases such as Noonan'ssyndrome, Costello syndrome, (faciocutaneoskeletal syndrome), leopardsyndrome, cardio-faciocutaneous syndrome (CFC), and neural crestsyndrome abnormalities causing cardiovascular, skeletal, intestinal,skin, hair and endocrine diseases.

c-Raf-1: Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viraloncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25(symbol: RAF1). c-Raf-1 can be targeted to the mitochondria by BCL2(i.e., oncogene B-cell leukemia 2) which is a regulator of apoptoticcell death. Active c-Raf-1 improves BCL2-mediated resistance toapoptosis, and c-Raf-1 phosphorylates BAD (i.e., BCL2-binding protein).c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lungand renal cell carcinoma. C-Raf-1 is also implicated as an importantmediator of tumor angiogenesis (Hood, J. D. et al., 2002, Science 296,2404). C-Raf-1 inhibitors may also be useful for the treatment of acutemyeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des2002, 8(25):2243-8). Raf-1 activators may be useful as treatment forneuroendocrine tumors, such as medullary thyroid cancer, carcinoid,small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,Anticancer Drugs 2006, 17(2):139-42). C-Raf-11 inhibitors may be usefulin treating colorectal, ovarian, lung and renal cell carcinoma, acutemyeloid leukemia, myelodysplastic syndromes, tumor angiogenesis, andneuroendocrine tumors such as medullary thyroid cancer, carcinoid, smallcell lung cancer and pheochromocytoma.

Brk: Target kinase Brk (i.e. breast tumor kinase, also known as PTK6) isa 51.8 kDa non-receptor tyrosine kinase encoded by human chromosome20q13.3 (symbol: BRK). The kinase has an SH3 domain, an SH2 domain, anda catalytic domain. In normal tissues, the expression of Brk (breasttumor kinase) is restricted to differentiating epithelial cells of theskin and gastrointestinal tract. According to Harvey and Crompton, Brkis expressed in over 60% of breast carcinoma tissue samples and breasttumour cell lines, but not normal mammary tissue or benign lesions. Theyused RNA interference to efficiently and specifically downregulate Brkprotein levels in breast carcinoma cells, and determined that thisresults in a significant suppression of their proliferation (Harvey andCrompton, Oncogene, 2003, 22(32): 5006-5010). Lin et al. identifiedprotein-tyrosine kinases that may be involved in the development andprogression of head and neck squamous cell carcinoma (HNSCC), and theirfindings suggest that the signaling pathways mediated through EphA1,Brk, and Ron may be involved in the development and progression of HNSCC(Lin et al., Arch Otolaryngol Head Neck Surg. 2004, 130(3):311-6). Lloret al. examined BRK expression in the normal gastrointestinal tract,colon tumor cell lines, and primary colon tumor samples and showed BRKis expressed in normal epithelial cells of the gastrointestinal tractthat are undergoing terminal differentiation. BRK expression alsoincreased during differentiation of the Caco-2 colon adenocarcinoma cellline. Modest increases in BRK expression were detected in primary colontumors by RNase protection, in situ hybridization, andimmunohistochemical assays (Llor et al., Clin Cancer Res. 1999,5(7):1767-77). Brk inhibitors may be useful in treating cancer, such asbreast and colon cancer, and head and neck squamous cell carcinoma.

Btk: Target kinase Btk (i.e., Bruton's tyrosine kinase) is a 76.3 kDatyrosine kinase encoded by chromosome Xq21.33-q22 (symbol: BTK). Themature kinase comprises a PH (i.e., Pleckstrin homology) domain, a BTK(i.e., Bruton's tyrosine kinase motif) motif, two SH3 domains, and a TKdomain. Mao et al. determined the X-ray crystal structure of the Btkkinase domain in its unphosphorylated state to 2.1-angstrom resolution(Mao et al., J. Biol. Chem., 2001, 276:41435).

As a member of the BTK/Tec family of protein tyrosine kinases (i.e.,PTKs), cytoplasmic Btk is involved in signal transduction pathwaysregulating growth and differentiation of B-lineage lymphoid cells(Rawlings, D. J., and Witte, O, N., 1994. Immunol. Rev. 138:105-119;Kurosaki, T., 1997, Curr Opin. Immunol 9:309-318; Uckun, F. M., 1998,Biochemical Pharmacology 56:683-691). As such, Btk participates insignal transduction pathways initiated by the binding of a variety ofextracellular ligands to their cell surface receptors. For example,following ligation of B cell antigen receptors (BCR), Btk activation bythe concerted actions of the PTKs Lyn and Syk (Kurosaki, T. (1997) CurrOpin. Immunol. 9, 309-318) is required for induction of phospholipaseC-[gamma]2 mediated calcium mobilization (Kurosaki, T., 1997, Curr Opin.Immunol. 9:309-318). Furthermore, Btk regulates B cell antigenreceptor-mediated JNK1 response through Rac1 and phospholipase C-gamma2activation.

Mutations in the human BTK gene are the cause of X-linkedagammaglobulinemia (XLA), a male immune deficiency disordercharacterized by a lack of mature, immunoglobulin producing, peripheralB cells (Tsukada, S., et al. (1993) Cell 72, 279-290; and Vetrie, D., etal. (1993) Nature 361, 226-233) and associated with a failure of Igheavy chain rearrangement. Patients are unusually prone to bacterialinfection but not to viral infection. A clinical picture resemblingrheumatoid arthritis develops in many. Before antibiotics, deathoccurred in the first decade. In the more usual X-linked form of thedisease, plasma cells are lacking. A rarer form of agammaglobulinemia(Hitzig, W. H et al. 1961, Med. Wschr., 91:1625), which is inherited asan autosomal recessive, shows marked depression of the circulatinglymphocytes, and lymphocytes are absent from the lymphoid tissue,Mensink et al. (Clin. Genet., 1987, 31:91) mapped XLA to Xq21.3-q22.Schwaber (Clin. Invest., 1992, 89:2053) presented direct evidence thatof a failure of V(D)J recombination which causes arrest in thetransition from pre-B cell to B lymphocyte. XLA patients have beenclassified in 2 general groups: those presenting at an early age withparticularly severe infections and those with less severe disease inwhich production of immunoglobulin is sustained at low-to-normal levelswell into the first decade of life. In the latter cases, an oncogeneticchange may occur in which the defective tyrosine kinase no longer cansustain the B-cell population, and a progressive reduction inimmunoglobulin production occurs (Ohta, Y et al., Proc. Nat. Acad. Sci.,1994, 91:9062)

Btk is an inhibitor of the Fas/APO-1 death inducing signaling complex(DISC) in B-lineage lymphoid cells (Vassilev, A., et al., 1998, J. Biol.Chem., 274:1646-1656). Additionally, Btk prevents ceramide- andvincristine-induced apoptosis. The fate of leukemia/lymphoma cells mayreside in the balance between the opposing proapoptotic effects ofcaspases activated by DISC and an upstream anti-apoptotic regulatorymechanism involving Btk and/or its substrates (Vassilev, A., et al.,1998, J. Biol. Chem. 274:1646-1656).

Accordingly, inhibitors of Btk are likely to enhance the drugsensitivity of B-lineage (e.g. leukemia/lymphoma such as acutelymphocytic leukemia) cells. Thus, pharmacological agents withBtk-modulatory activity can be used as chemosensitizing agents fortreating Btk-expressing malignancies or diseases caused by proliferationand antibody production of BTK-expressing B-cells, and as B-cellreconstituting agents in humoral immunodeficiencies with decreasednumbers or absence of B-cells. Furthermore, Btk modulating agents areuseful as immunosuppressive agents for prevention of hyperacuterejection of organs in transplantation, which is directed by B-cells,autoimmune diseases, and conversion of immunity to drugs (e.g.antibodies or biologicals) or blood products (e.g. coagulation factorssuch as Factor VIII) in patients who develop antibodies to such agents.

Significant additional research has defined the role of Btk in the cell.For example, Cheng et al. (Proc. Nat. Acad. Sci., 1994, 91:8152) showedthat Btk interacts with the SH3 domains of Fyn, Lyn, and Hck, all ofwhich are activated upon stimulation of B- and T-cell receptors. Thesefindings extended the range of interactions mediated by SH3 domains andprovide indication of a link between Btk and previously establishedsignaling pathways in B lymphocytes. Further, linkage studies involving1,114 progeny backcross revealed colocalization of X-linkedimmunodeficiency (xid) mutation in mice with the BTK gene for (Thomas,J. D. et al., Science 1993, 261:355). And further, Uckun et al. (Uckun,F. M et al. 1996, Science 273: 1096) reported that DT-40 lymphoma Bcells rendered Btk deficient through targeted disruption of the BTK genedid not undergo radiation-induced apoptosis. Finally, Btk plays a keyrole in endotoxin-induced TNFα release from monocytes (Horwood, N. J. etal., J. Exp. Med. 2003, 197:1603).

Btk inhibitors may be useful in treating multiple sclerosis, systemiclupus erythematosis, rheumatoid arthritis, and Graves' disease, inaddition to the diseases discussed above.

Cyclin dependent kinases: The cyclin dependent kinases (Cdk) play amajor role in the signaling of cell cycles. The Cdk binds cyclin proteinto form complex involved in the various stages of the cell cycle.Aberrant cell cycle progression occurs in cancers, often involving theactivity of Cdk, such that inhibitors of Cdk are potential anti-cancertherapeutics.

Cdk2: Target kinase Cdk2 (i.e., Cyclin dependent kinase 2) is a 33.9 kDaserine/threonine kinase (STK) encoded by chromosome 12q13 (symbol:CDK2). Cdk2 is also known as p33 protein kinase, and cell divisionprotein kinase 2. De Bondt et al. reported the X-ray crystallographicstructure of Cdk2 (De Bondt et al., Nature 1993, 363: 595-602). Cdk2 isinvolved in control of the human cell cycle. Cdk2 activation requiresassociation with cyclins and leads to cell proliferation. Further,inhibition of cellular proliferation occurs upon association ofinhibitors (e.g., cyclin-dependent kinase inhibitor 113B) with thecyclin-Cdk2 complex. Cyclin E/Cdk2 complexes play a role incarcinogenesis, for example, Cdk2 amplification is associated withconcurrent Cyclin E amplification in several cancers, includingcolorectal and ovarian cancer (Kitahara et al., Int. J. Cancer, 1995,53: 1986-1989; Marone et al., Int. J. Cancer, 1998, 75: 31-39). Teixeiraet al. show that retinoic acid inhibits cell cycle progression of MCF-7human breast cancer cells by inhibiting cdk2 mRNA and protein productionand by decreasing cdk2 activity (Teixeira et al., Mol Endocrinol 1997,11(9):1191-202). Cipriano and Chen studied the TGF-beta1 effect onnormal human prostate and carcinoma cells, and showed that normal cellswere sensitive to growth inhibition, whereas tumor cells were not oronly minimally inhibited regardless of the concentration of TGF-beta1,and correlated these results to Cdk2 activity. Their results indicatethat a lack of inhibition of the Cdk2 activity correlates withinsensitivity to TGF-beta1 in prostate tumor cells (Cipriano and Chen,Oncogene 1998, 17(12):1549-56). Cdk2 inhibitors may be useful intreating cancer, including prostate, breast, colorectal and ovariancancer.

Cdk4: Target kinase Cdk4 (i.e., Cyclin dependent kinase 4) is a 33 kDaSTK encoded by chromosome 12q14 (symbol: CDK4). Lam et al. reportedexpression of CDK4 and CDK6 was elevated relative to matched normalbrain tissue in eight of 18 glioblastoma multiforme (GBM) tumours (44%).Their data attests to the functional importance of both CDK4 and CDK6 inastrocytic tumorigenesis, particularly during the later stages of tumourprogression (Lam et al., Br J Neurosurg 2000, 14(1):28-32). Backlund etal. found that loss of both wild-type copies of any of the three tumoursuppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4,disrupting the Rb1 pathway, were associated with shorter survival inanaplastic astrocytoma patients (Backlund et al., Br J Cancer 2005,93(1):124-30). Yu et al. report that the ability of cyclin D1 toactivate cyclin-dependent kinase CDK4 underlies the critical role forcyclin D1 in breast cancer formation. They also found that the continuedpresence of CDK4-associated kinase activity is required to maintainbreast tumorigenesis (Yu et al., Cancer Cell 2006, 9(1):23-32). Cdk4inhibitors may be useful in treating cancer, including glioblastoma(e.g. glioblastoma multiforme), anaplastic astrocytoma, and breastcancer.

Cdk5: Target kinase Cdk5 (i.e., Cyclin dependent kinase 5) is a 33.3 kDaSTK encoded by chromosome 7q36 (symbol: CDK5). Cruz et al. state thatproteolytic cleavage of p35 generates p25, leading to aberrant Cdk5activation. The accumulation of p25 is implicated in severalneurodegenerative diseases. Their findings provide compelling evidencethat in vivo deregulation of Cdk5 by p25 plays a causative role inneurodegeneration and the development of neurofibrillary pathology (Cruzet al., Neuron 2003, 40(3):471-83). Takahashi et al. investigated theCdk5 distribution pattern in diffuse Lewy body disease brains usingimmunohistochemistry. Their data suggest that Cdk5 may be associatedwith Lewy body formation (Takahashi et al., Brain Res 2000,862(1-2):253-6). Cdk5 inhibitors may be useful in treatingneurodegenerative disorders, including Alzheimer's disease, amyotrophiclateral sclerosis and Lewy body disease.

Cdk6: Target kinase Cdk6 (i.e., Cyclin dependent kinase 6) is a 36.9 kDaSTK encoded by chromosome 7q21-q22 (symbol: CDK6). Lain et al. reportedexpression of CDK4 and CDK6 was elevated relative to matched normalbrain tissue in eight of 18 glioblastoma multiforme (GBM) tumours (44%).Their data attests to the functional importance of both CDK4 and CDK6 inastrocytic tumorigenesis, particularly during the later stages of tumourprogression (Lam et al., Br J Neurosurg 2000, 14(1):28-32). Costello etal., applied restriction landmark genomic scanning to matched samples ofglioma and normal brain DNA and found tumor-specific amplification ofthe gene encoding cyclin-dependent kinase 6 (CDK6). They alsocorroborated this finding by identifying both amplification-associatedand amplification-independent increases in CDK6 protein levels ingliomas relative to matched normal brain samples (Costello et al.,Cancer Res 1997, 57(7): 1250-4). Corcoran et al. found in two samplesfrom patients with splenic lymphoma with villous lymphocytes (SLVL), theCDK6 protein was markedly over expressed. They suggest thatdysregulation of CDK6 gene expression contributes to the pathogenesis ofSLVL and splenic marginal zone lymphoma (SMZL) (Oncogene 1999,18(46):6271-7). Chilosi et al. provide evidence that CDK6 is abnormallyexpressed in T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) and maybe involved in the pathogenesis of this malignancy (Chilosi et al., Am JPathol 1998, 152(1):209-17). Cram et al. show that Indole-3-carbinol(I3C) can induce a G(1) cell cycle arrest of human MCF-7 breast cancercells that is accompanied by the selective inhibition ofcyclin-dependent kinase 6 (CDK6) expression (Cram et al., J Biol Chem2001, 276(25):22332-40). Cdk6 inhibitors may be useful in treatingcancer, including glioblastoma multiforme, non-Hodgkin's lymphoma,splenic marginal zone lymphoma, T-cell lymphoblastic lymphoma (T-LBL)and T-cell acute lymphoblastic leukemia (T-ALL).

CHK1: Target kinase Chk1 (i.e., Checkpoint kinase) is a 54.4 kDa STKencoded by chromosome 11q24 (symbol: CHEK1, CHK1). CHK1 is involved inDNA damage checkpoint. Carassa et al., to understand the role of Chk1and Chk2 in the cellular response to different anticancer agents,knocked down the expression of each protein or simultaneously of bothproteins by using the small interfering RNA technique in a HCT-116 coloncarcinoma cell line and in its isogenic systems in which p53 and p21 hadbeen inactivated by targeted homologous recombination. They show thatinhibition of Chk1 but not of Chk2 in p21(−/−) and p53(−/−) cells causeda greater abrogation of G(2) block induced by ionizing radiation andcis-diamine-dichloroplatinum treatments and a greater sensitization tothe same treatments than in the parental cell line with p53 and p21 wildtype proteins. Their data further emphasise the role of Chk1 as amolecular target to inhibit in tumors with a defect in the G(1)checkpoint with the aim of increasing the selectivity and specificity ofanticancer drug treatments (Carrassa et al., Cell Cycle 2004,3(9):1177-81). Similarly, studies by Hirose et al. focused on themechanism by which Temozolomide (TMZ) induces G(2)-M arrest and onwhether inhibition of such G(2)-M arrest might sensitize glioma cells toTMZ-induced toxicity. U87MG glioma cells treated with TMZ underwentG(2)-M arrest associated with Chk1 activation and phosphorylation ofboth cdc25C and cdc2. These TMZ-induced effects were inhibited by theChk1 kinase inhibitor UCN-01. Although not in itself toxic, UCN-01increased the cytotoxicity of TMZ 5-fold, primarily by inhibitingcellular senescence and increasing the percentage of cells bypassingG(2)-M arrest and undergoing mitotic catastrophe. In addition toenhancing TMZ-induced cytotoxicity in p53-proficient cells, UCN-01 alsoblocked TMZ-induced Chk1 activation and transient G(2)-M arrest inp53-deficient U87MG-E6 cells and similarly enhanced TMZ-induced mitoticcatastrophe and cell death. Taken together, their results indicate thatChk1 links TMZ-induced DNA mismatch repair to G(2)-M arrest.Furthermore, inhibition of the cytoprotective G(2) arrest pathwaysensitizes cells to TMZ-induced cytotoxicity and may represent a novel,mechanism-based means of increasing TMZ efficacy in both p53 wild-typeand p53 mutant glioma cells. (Hirose et al., Cancer Res 2001,61(15):5843-9). As such, CHK1 inhibitors may be used in combinationtherapy to improve the therapeutic efficacy of chemotherapeutic drugs.CHK1 inhibitors may be useful in combination with chemotherapeutic drugsin treating cancer.

Csk: Target kinase Csk (i.e., c Src kinase) is a 50.7 kDa tyrosinekinase encoded by chromosome 15q23-q25 (symbol: CSK). Csk, cloned byPartanen et al. (Oncogene 1991, 6: 2013-2018), is a cytoplasmic tyrosinekinase that downregulates the tyrosine kinase activity of the Srconcoprotein through tyrosine phosphorylation of the Src carboxyterminus. Activation of Csk may be therapeutic for cancers in which Srcis activated, such as in colon and pancreatic carcinomas (Lutz et al.,Biochem Biophys Res Commun 1998, 243(2):503-8; Cam et al., Cancer 2001,92(1):61-70). Zheng and She state that the lymphoid-specific phosphatase(LYP) encoded by PTPN22 is involved in preventing spontaneous T-cellactivation by dephosphorylating and inactivating T-cellreceptor-associated Csk kinase. They genotyped 396 type 1 diabeticpatients and 1,178 control subjects of Caucasian descent from northcentral Florida and report a strong association between type 1 diabetesand a polymorphism (R620W) in the PTPN22 gene. In vitro experiments haveshown that the mutant 620W LYP protein (1858T) does not bind Csk.Together with previous reports of the association between PTPN22 andtype 1 diabetes, as well as rheumatoid arthritis and systemic lupuserythematosus, these results provide compelling evidence that LYP is acritical player in multiple autoimmune disorders (Zheng and She,Diabetes 2005, 54(3):906-8). Csk modulators, including inhibitors, maybe useful in treating autoimmune diseases, including type 1 diabetes,rheumatoid arthritis and systemic lupus erythematosus.

EGFR: Target kinase EGFR (i.e., Epidermal Growth Factor Receptor) is a134.3 kDa transmembrane tyrosine kinase coded by chromosome 7p12.3-p12.1(symbol: EGFR). OMIM indicates that EGF enhances phosphorylation ofseveral endogenous membrane proteins, including EGFR. EGFR has 2components of different molecular weight; both contain phosphotyrosineand phosphothreonine but only the higher molecular weight form containsphosphoserine (Carlin and Knowles, Proc. Nat. Acad. Sci. 1982, 79:5026-5030.). Carlin et al. (Cytogenet. Cell Genet. 1982, 32: 256) showedthat the specific cell surface antigen previously called SA7 (Aden andKnowles, Immunogenetics 1976, 3: 209-211) is identical to EGFR. EGFRsignaling involves small GTPases of the Rho family, and EGFR traffickinginvolves small GTPases of the Rab family. Lanzetti et al. (Nature 2000,408: 374-377) reported that the EPS8 protein connects these signalingpathways. EPS8 is a substrate of EGFR that is held in a complex withSOS1 by the adaptor protein E3B1, thereby mediating activation of RAC.Through its SH3 domain, EPS8 interacts with RNTRE. Further, Lanzetti etal. (ibid) showed that RNTRE is a RAB5 GTPase-activating protein whoseactivity is regulated by EGFR. By entering in a complex with EPS8, RNTREacts on RAB5 and inhibits internalization of EGFR. Furthermore, RNTREdiverts EPS8 from its RAC-activating function, resulting in theattenuation of RAC signaling. Thus, depending on its state ofassociation with E3B1 or RNTRE, EPS8 participates in both EGFR signalingthrough RAC and EGFR trafficking through RAB5 (OMIM MIM Number: 131550:Dec. 16, 2005).

EGFR is implicated in breast cancer, colorectal, and bladder cancer, andmodulation of EGFR activity is a therapeutic route to amelioration ofthese pathologic states (Xu et al., Mol Cancer Ther 2005, 4(3):435-42).An important umnet need has emerged in non small cell lung cancerpatients who initially respond to treatment with EGFR inhibitors butthen develop resistance to the initial drug (Koboyashi, S. et al. N EnglJ. Med. 2005, 352:786-92). EGFR is also a possible target for treatingglioblastoma multifone (Raizer, J Neurooncol 2005, 74(1):77-86), andsquamous cell carcinomas, for example in the esophagus (Hanawa et al.,Int J Cancer 2006, 118(5):1173-80), head and neck (Hambek et al.,Anticancer Res 2004, 24(6):3881-6), and oral cavity and tongue (Ekberget al., Int J Oncol 2005, 26(5):1177-85). Unlu and Leake studied theeffect of epidermal growth factor (EGF) and a specific inhibitor ofEGFR, on the growth and invasiveness of the prostate cancer cell linesPC3 and DU145. Their results indicate that EGF is a potent stimulativeagent for both growth and invasion in prostate cancer cells, and thattargeting the EGFR function inhibits not only tumor growth but alsoinvasiveness (Unlu and Leake, Int J Biol Markers 2003, 18(2):139-46).EGFR inhibitors may be useful in treating cancer, including breast,colon, bladder, prostate and non small cell lung cancer, squamous cellcarcinomas of the head and neck, oral cavity, and esophagus, andglioblastoma multiforme.

EphA1: Target kinase EphA1 (i.e., Ephrin Receptor A1) is a 108.1 kDatyrosine kinase encoded by chromosome 7q32-q34 (symbol: EPHA1). OMIMindicates that the EPH and EPH-related receptors comprise the largestsubfamily of receptor protein-tyrosine kinases. They have beenimplicated in mediating developmental events, particularly in thenervous system. Receptors in the Eph subfamily typically have a singlekinase domain and an extracellular region containing a Cys-rich domainand 2 fibronectin type III repeats. The ligands for Eph receptors havebeen named “ephrins” by the Eph Nomenclature Committee (Cell 1997, 90:403-404). Based on their structures and sequence relationships, ephrinsare divided into the ephrin-A (EFNA) class, which are anchored to themembrane by a glycosylphosphatidylinositol linkage, and the ephrin-B(EFNB) class, which are transmembrane proteins. The Eph family ofreceptors are divided into 2 groups based on the similarity of theirextracellular domain sequences and their affinities for binding ephrin-Aand ephrin-B ligands. The Eph Nomenclature Committee (ibid.) proposedthat Eph receptors interacting preferentially with ephrin-A proteins becalled EphA and Eph receptors interacting preferentially with ephrin-Bproteins be called EphB. Maru et al. (1988) reported characterization ofthe novel receptor tyrosine kinase gene, EPH. The splicing points ofkinase domain-encoding exons were completely distinct from those ofother protein tyrosine kinase genes, suggesting that this is theearliest evolutionary split within this family. In Northern blotanalysis, EPH gene mRNA was detected in liver, lung, kidney, and testesof rat; screening of 25 human cancers of various cell types showedpreferential expression in cells of epithelial origin. Overexpression ofEPH mRNA was found in a hepatoma and a lung cancer without geneamplification. Southern blot analysis of DNAs from human-mouse hybridclones with an EPH probe showed that this gene is present on humanchromosome 7. Two other receptor tyrosine kinase genes, MET and EGFR,are on the same chromosome. By in situ hybridization, Yoshida et al.(1989) assigned the EPH locus to 7q32-q36. Although ephrins form ahigh-affinity multivalent complex with their receptors present on axons,axons can be rapidly repelled rather than being bound (OMIM MIM Number:179610: Sep. 5, 2000). Lin et al. identified 5 PTIKs that wereoverexpressed in head and neck squamous cell carcinoma (HNSCC) using areverse transcriptase-PCR technique and confined the overexpression of 3known PTKs in some of the 8 archival HNSCC specimens studied. Theirfinding suggests that the signaling pathways mediated through EphA1,Brk, and Ron may be involved in the development and progression of HNSCC(Lin et al., Arch Otolaryngol Head Neck Surg 2004, 130(3):311-6). EphA11inhibitors may be useful in treating cancer, including liver and lungcancer, and head and neck squamous cell carcinoma.

EphA2: Target kinase EphA2 (i.e., Ephrin Receptor A2) is a 108.3 kDatyrosine kinase encoded by chromosome 1p36.1 (symbol: EPHA2). EphA2,similar to other ephrin receptors, is found in epithelial, lymphoid, andespecially neuron tissue where EphA2 is critically involved inshort-range contact-mediated axonal guidance. Further, EphA2 is highlyexpressed in metastatic melanoma cells. Ephrin A1, a ligand for EphA2,was shown to be up regulated during melanoma progression (Easty et al.,Int J Cancer 1999, 84(5):494-501). Hattori et al. showed that ephrin-A2forms a stable complex with the metalloproteinase Kuzbanian, involvinginteractions outside the cleavage region and the protease domain. Ephreceptor binding triggered ephrin-A2 cleavage in a localized reactionspecific to the cognate ligand. The cleavage-inhibiting mutation inephrin-A2 delayed axon withdrawal. Hattori et al. (ibid) concluded thattheir studies reveal mechanisms for protease recognition and control ofcell surface proteins, and, for ephrin-A2, they may provide a means forefficient axon detachment and termination of signaling (Hattori et al.,Science 2000, 289: 1360-1365). Ireton and Chen review EphA2 as apromising target for cancer therapeutics, indicating EphA2 isoverexpressed in breast, prostate, lung, and colon cancers (Ireton andChen, Curr Cancer Drug Targets 2005, 5(3): 149-57). Landen et al. statethat EphA2 is involved in many processes crucial to malignantprogression, such as migration, invasion, metastasis, proliferation,survival and angiogenesis. Inducing EphA2 downregulation by any one ofseveral mechanisms (antibody-mediated inhibition of signalling,antibody-mediated downregulation of total EphA2 expression andsiRNA-mediated inhibition of expression) has been shown to decreasetumour growth, prolong survival and inhibit angiogenesis in multiplepreclinical models of ovarian, breast and pancreatic cancer. TargetingEphA2 is especially attractive in ovarian cancer, in whichoverexpression is present in >75% of cases (Landen et al., Expert OpinTher Targets 2005, 9(6):1179-87). Abraham et al. state that the clinicalsignificance of the expression of EphA2 was observed in breast,prostate, colon, skin, cervical, ovarian, and lung cancers. They studiedEphA2 to determine the expression of EphA2 and its ligand, Ephrin A-1,and E-cadherin in carcinoma of the urinary bladder, and determine EphA2as a new target for therapy in bladder cancer. They conclude EphA2 mayserve as a novel target for bladder cancer therapy, (Abraham et al.,Clin Cancer Res 2006, 12(2):353-60). EphA2 inhibitors may be useful intreating cancer, including bladder, breast, prostate, colon, skin,cervical, ovarian, pancreatic, and lung cancer and melanoma.

EphB2: Target kinase EphB2 (i.e., Ephrin Receptor B2) is a 117.5 kDatransmembrane tyrosine kinase encoded by chromosome 1p36.1-p35 (symbol:EPHB2). Mann et al. state that forward and reverse signaling mediated byEphB tyrosine kinase receptors and their transmembrane ephrin-B ligandsplay important roles in axon pathfinding. In their investigations ofgrowth cones from the ventral (EphB receptor-bearing) and dorsal(ephrin-B-bearing) embryonic Xenopus retina designed to investigate thesignaling mechanisms in both forward and reverse directions, it isreported that unclustered, but not clustered. EphB2 ectodomains triggerfast (5-10 min) transient collapse responses in growth cones. Thiscollapse response is mediated by low levels of intracellular cyclic GMPand requires proteasome function. In contrast, clustered, but notunclustered, ephrin-B1 ectodomains cause slow (30-60 min) growth conecollapse that depends on high cGMP levels and is insensitive toinhibition of the proteasomal pathway. Upon receptor-ligand binding,endocytosis occurs in the reverse direction (EphB2-Fc into dorsalretinal growth cones), but not the forward direction, and is alsosensitive to proteasomal inhibition. Endocytosis is functionallyimportant because blocking of EphB2 internalization inhibits growth conecollapse. They state their data reveals that distinct signalingmechanisms exist for B-type Eph/ephrin-mediated growth cone guidance andsuggest that endocytosis provides a fast mechanism for switching offsignaling in the reverse direction (Mann et al., J Neurobiol 2003,57(3):323-36). Nakada et al. demonstrate that migrating glioblastomacells overexpress EphB2 in vitro and in vivo; glioma migration andinvasion are promoted by activation of EphB2 or inhibited by blockingEphB2. Dysregulation of EphB2 expression or function may underlie gliomainvasion (Nakada et al., Cancer Res 2004, 64(9):3179-85). Wu et al.,investigated the expression of EphB2 and EphB4 in breast carcinomas.Clinicopathological and survival correlations were statisticallyanalyzed in a series of 94 breast carcinomas, 9 normal specimens and 4breast carcinoma cell lines. Both EphB2 and EphB4 RTPCR products couldbe detected in all specimens. Increased EphB2 protein expression wasnegatively associated with overall survival (Wu et al., Pathol Oncol Res2004, 10(1):26-33). Hafner et al. studied expression profiles of 12different Eph receptors and 8 ephrins in human lung, colorectal, kidney,liver, and brain cancers. They report EphB2 was up-regulated 9-fold inhepatocellular carcinoma (Hafner et al., Clinical Chemistry 2004,50:490-99). Umeda et al. studied the expression of ephrinB2 and EphBreceptors within fibroproliferative membranes in patients with ocularangiogenic diseases collected during vitrectomy. EphB2 and EphB3expression was observed on fibroproliferative membranes that wereharvested from patients with proliferative diabetic retinopathy (EphB2,90.0%; EphB3, 70.0%) and retinopathy of prematurity (EphB2, 35.0%;EphB3, 45.0%). Their data suggest that the ephrinB2-EphB2/B3 system mayplay an important role in ocular angiogenesis (Umeda et al., Am JOphthalmol 2004, 138(2):270-9). EphB2 inhibitors may be useful intreating cancer, including breast cancer, hepatocellular carcinoma andglioblastoma, and for use in treating ocular angiogenesis diseases,including retinopathy (e.g. retinopathy of prematurity and proliferativediabetic retinopathy).

EphB4: Target kinase EphB4 (i.e., Ephrin Receptor B4) is a 108.3 kDatransmembrane tyrosine kinase encoded by chromosome 7q22 (symbol:EPHB4). EphB4 belongs to the Eph family of receptor tyrosine kinases.Developmental studies have shown that the Eph receptors, by regulatingcell adhesion and cell movement in the embryo, are important for theproper organization and integrity of tissues. Because tissuedisorganization and abnormal cell adhesion, movement, and survivalcharacterize the more advanced stages of cancer, the inappropriatefunctioning of an Eph receptor in breast tumor cells enhancesmalignancy. Xia et al. studied the biological function of the receptortyrosine kinase EphB4 in bladder cancer. All of nine bladder cancer celllines examined expressed EphB4. Further, they showed EphB4 knockdownusing specific siRNA and antisense oligodeoxynucleotides molecules ledto a profound inhibition in cell viability associated with apoptosis viaactivation of caspase-8 pathway and downregulation of antiapoptoticfactor, bcl-xl. Furthermore, EphB4 knockdown significantly inhibitedtumor cell migration and invasion. EphB4 knockdown in an in vivo murinetumor xenograft model led to a nearly 80% reduction in tumor volumeassociated with reduced tumor proliferation, increased apoptosis andreduced tumor microvasculature (Xia et al., Oncogene 2006,25(5):769-80). Xia et al. also studied the expression and biologicalrole of EphB4 in prostate cancer. They found EphB4 mRNA is expressed in64 of 72 (89%) prostate tumor tissues assessed and EphB4 proteinexpression is found in the majority (41 of 62, 66%) of tumors, and 3 of20 (15%) normal prostate tissues. They also showed knockdown of theEphB4 protein using EphB4 short interfering RNA or antisenseoligodeoxynucleotide significantly inhibits cell growth/viability,migration, and invasion, and induces apoptosis in prostate cancer celllines (Xia et al., Cancer Res 2005, 65(11):4623-32). Lee et al. usedRT-PCR, western blotting and immunohistochemical techniques to examineEphB4 expression and protein levels in human prostate cancer cell linesLNCaP, DU145 and PCJ. Immunohistochemistry was also used to examinelocalisation of EphB4 in tissue samples from 15 patients with prostatecarcinomas. All three prostate cancer cell lines expressed the EphB4gene and protein. EphB4 immunoreactivity in vivo was significantlygreater in human prostate cancers as compared with matched normalprostate epithelium and there appeared to be a trend towards increasedexpression with higher grade disease (Lee et al., BMC Cancer 2005,5:119). Stephenson et al. used commercially available cDNA arrays toidentify EphB4 as a gene that is up-regulated in colon cancer tissuewhen compared with matched normal tissue from the same patient(Stephenson et al., BMC Mol Biol 2001, 2:15). Takai et al. usedfluorescent immunohistochemistry to analyze serial frozen sections of 20endometrial carcinomas and 20 normal endometria for EphB4 and ephrin-B2protein expression. Further, they analyzed the relationship between thepatient's characteristics and the percentages of EphB4- andephrin-B2-stained cells. They indicate the results demonstrate thatincreased EphB4 and ephrin-B2 expression may reflect or induce inendometrial carcinomas increased potential for growth and tumorigenicity(Takai et al., Oncol Rep 2001, 8(3):567-73). Sinha et al., studiedexpression of EphB4 in six men with primary squamous cell carcinoma ofthe head and neck (HNSCC) that had metastasized to the cervical lymphnodes. They obtained specimens of the primary tumor, the nodalmetastasis, and the adjacent normal mucosa, and performedimmunocytochemistry on each. They observed EphB4 expression in allprimary and metastatic tumors and no expression in the normal tissue. Ineach of the six patients, expression was greater in the metastatic tumorthan in the primary tumor (Sinha et al., Ear Nose Throat J 2003,82(11):866, 869-70, 887). EphB4 inhibitors may be useful in treatingcancer, including breast, bladder, prostate, colon, and endometrialcancers and head and neck squamous cell carcinoma.

Erk2: Target kinase Erk2 (i.e., extracellular signal-regulated kinase 2)is a 41.4 kDa dual function serine/threonine-tyrosine kinase encoded bychromosome 22q11.2 (symbol: MAPK1). Erk2 is a member of themitogen-activated protein (MAP) kinase family and is alternatively knownas mitogen-activated protein kinase 1 (i.e., MAPK1). MAP kinases act asan integration point for multiple biochemical signals, and are involvedin a wide variety of cellular processes such as proliferation,differentiation, transcription regulation and development.

The activation of Erk2 requires phosphorylation by upstream kinases.Upon activation, Erk2 translocates to the nucleus of the stimulatedcells, where it phosphorylates nuclear targets, in addition to othertargets including microtubule associated protein 2, myelin basic proteinand ELK1. MacKenzie et al. state that the cAMP-specificphosphodiesterase family 4, subfamily D, isoform 3 (i.e., PDE4D3) isshown to have FQF (i.e., Phe-Gln-Phe) and KIM (i.e., Kinase InteractionMotif) docking sites for Erk2. These sites straddle the Ser(579) targetresidue for Erk2 phosphorylation of PDE4D3. Mutation of either or bothof these docking sites prevent Erk2 from being co-immunoprecipitatedwith PDE4D3, ablate the ability of epidermal growth factor (EGF) toinhibit PDE4D3 through Erk2 action in transfected COS cells, andattenuate the ability of Erk2 to phosphorylate PDE4D3 in vitro. The twoconserved NH(2)-terminal blocks of sequence, called upstream conservedregions 1 and 2 (i.e., UCR1 and UCR2), that characterize PDE4 longisoforms, are proposed to amplify the small, inherent inhibitory effectthat Erk2 phosphorylation exerts on the PDE4D catalytic unit. Incontrast to this, the lone intact UCR2 region found in PDE4D1 directsCOOH-terminal Erk2 phosphorylation to cause the activation of this shortisoform. From the analysis of PDE4D3 truncates, it is suggested thatUCR1 and UCR2 provide a regulatory signal integration module that servesto orchestrate the functional consequences of Erk2 phosphorylation. ThePDE4D gene thus encodes a series of isoenzymes that are either inhibitedor activated by Erk2 phosphorylation and thereby offers the potentialfor ERK2 activation either to increase or decrease cAMP levels incellular compartments (MacKenzie et al., J Biol Chem 2000,275(22):16609-17).

According to OMIM, Pleschka et al. (Nature Cell Biol., 2001, 3: 301-305)proposed that Erk2 regulates a cellular factor involved in the viralnuclear export protein function. They suggested that local applicationof MEK inhibitors may have only minor toxic effects on the host whileinhibiting viral replication without giving rise to drug-resistant virusvariants (OMIM MIM Number: 176948: Oct. 27, 2005). Erk2 is involved incytokine signaling and is a target for treating inflammation. Ramesh andPhilipp state that lipoproteins are the key inflammatory molecule typeof Borrelia burgdorferi, the spirochete that causes Lyme disease. Theyinvestigated whether specific inhibition of p38 and Erk1/2 MAPK wouldinhibit TNF-alpha and IL-6 production and thus astrocyte apoptosis, andproliferation, respectively. Lipoprotein-stimulated IL-6 production wasunaffected by the MAPK inhibitors. In contrast, inhibition of both p38and Erk1/2 significantly diminished TNF-alpha production, and totallyabrogated production of this cytokine when both MAPK pathways wereinhibited simultaneously. MAPK inhibition thus may be considered as astrategy to control inflammation and apoptosis in Lyme neuroborreliosis(Ramesh and Philipp, Neurosci Lett 2005, 384(1-2):112-6). The role ofErk2 in signaling of cell differentiation, proliferation and survivalsuggests that inhibition of Erk2 may be therapeutic for several types ofcancer. Husain et al. studied the effect of NSAIDs on MAPK activity andphosphorylation in gastric cancer. They conclude that NS-398 (aselective COX-2 inhibitor) and indomethacin (a non-selective NSAID)significantly inhibit proliferation and growth of human gastric cancercell line MKN28. This effect is mediated by NSAID-induced inhibition ofMAPK (ERK2) kinase signaling pathway, essential for cell proliferation(Husain et al., Life Sci 2001, 69(25-6):3045-54). Erk2 inhibitors may beuseful in treating cancer, including gastric cancer, and in treatinginflammation, including control of inflammation and apoptosis in Lymeneuroborreliosis.

Fak: Target kinase Fak (i.e., Focal adhesion kinase 1, aka proteintyrosine kinase 2, PTK2) is a 119.2 kDa tyrosine kinase encoded bychromosome 8q24.3 (symbol: PTK2). The structure of Fak comprises a B41(i.e., Band 4.1 homology) domain in addition to the TK domain. Fak and arelated protein Pyk2/CAK-beta are cytoplasmic non-receptor proteintyrosine kinases. Localization of Fak via its C-terminal Focal AdhesionTargeting domain to focal complexes/adhesions (sites of integrinreceptor clustering) is a prerequisite for Fak activation. Auto- ortrans-phosphorylation of Fak on Tyr397 allows for docking of the Srcfamily kinases, among other molecules. Src kinases phosphorylate Fak notonly on the Tyr residues in the activation loop of the FAK kinase, butalso create binding sites for downstream signaling components. Moreover,FAK can be activated by other receptors, linking them to the integrinsignaling pathway. Activation of FAK can promote cell spreading,locomotion, survival and anchorage-dependent growth.

FAK-related non-kinase (FRNK), the C-terminal portion of FAK isexpressed in some cell types by activating transcription from analternative promoter. FRNK is proposed to function as an endogenousinhibitor of Fak signaling.

The role of Fak in signaling of cell proliferation, migration, adhesionand survival may be targeted in therapeutics for several types ofcancer. Lightfoot et al. used immunohistochemical techniques to assessFAK expression in patients with fibrocystic disease (FCD), atypicalductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) andinfiltrating ductal carcinoma (IDC). The pattern of FAK expression inDCIS was significantly higher than AUDH (p<0.0001) and IDC (p=0.02).They conclude that FAK overexpression in preinvasive, DCIS tumorsprecedes tumor cell invasion or metastasis, suggesting that FAK mayfunction as a survival signal and be an early event in breasttumorigenesis (Lightfoot et al., Breast Cancer Res Treat 2004,88(2):109-16). Miyazaki et al. performed an immunohistochemical analysisof FAK protein expression to determine the relationship between FAKoverexpression and clinicopathological factors in oesophageal squamouscell carcinoma (ESCC). They concluded that FAK overexpression of ESCCwas related to cell differentiation, tumour invasiveness, and lymph nodemetastasis. Consequently, patients with ESCC who had FAK overexpressionhad a poor prognosis (Miyazaki et al., Br J Cancer 2003, 89(1):140-5).Smith et al. tested antisense oligonucleotide inhibitors of FAK, incombination with 5-fluorouracil (5-FU), to increase its sensitivity inhuman melanoma cell lines. They conclude their data show that thedownregulation of FAK by antisense oligonucleotide combined with 5-FUchemotherapy results in a greater loss of adhesion and greater apoptosisin melanoma cells than treatment with either agent alone, suggestingthat the combination may be a potential therapeutic agent for humanmelanoma in vivo (Smith et al., Melanoma Res 2005, 15(5):357-62). In areview, Natarajan et al. summarize data that has demonstrated 1)elevated FAK expression in anaplastic astrocytoma and glioblastoma tumorbiopsy samples, 2) a role for FAK in the promotion of glioblastoma cellproliferation, survival and migration in vitro, and 3) a role for FAK inthe promotion of glioblastoma cell proliferation in vivo in an animalmodel (Natarajan et al., Cancer J 2003, 9(2):126-33). Rovin et al.investigated FAK expression in human prostate specimens by usingimmunohistochemistry. In their conclusion, they suggest that thesustained elevated levels of FAK expression during prostate tumor cellprogression is consistent with a role for FAK in the development andmaintenance of prostate carcinoma (Rovin et al., Prostate 2002,53(2):124-32). Itoh et al. investigated whether focal adhesion kinase(FAK) is involved in the progression of human hepatocellular carcinoma(HCC). They conclude their data suggests that FAK plays an importantrole in promoting tumor progression, especially vascular invasion, inHCC (Itoh et al., Clin Cancer Res 2004, 10(8):2812-7). von Sengbusch etal. state that organ-specific tumor cell adhesion to extracellularmatrix (ECM) components and cell migration into host organs ofteninvolve integrin-mediated cellular processes that can be modified byenvironmental conditions acting on metastasizing tumor cells, such asshear forces within the blood circulation. Since the focal adhesionkinase (FAK) appears to be essential for the regulation of theintegrin-mediated adhesive and migratory properties of tumor cells, theyinvestigated its role in early steps of the metastatic cascade using invitro and in vivo approaches. They summarize that FAK appears to beinvolved in early events of integrin-mediated adhesion of circulatingcarcinoma cells under fluid flow in vitro and in vivo. This kinase maytake part in the establishment of definitive adhesive interactions thatenable adherent tumor cells to resist fluid shear forces, resulting inan organ-specific formation of distant metastases (von Sengbusch et al.,Am J Pathol 2005, 166(2):585-96).

Westhoff et al., note that elevated expression of the nonreceptortyrosine kinases Src and Fak correlates with malignancy potential andpoor clinical prognosis in colon and breast tumors. They also state thatrecent studies monitoring focal adhesion dynamics in cells deficient forFak and Src implicate Src and Fak as critical mediators of integrinadhesion turnover that promote cell migration. Cells devoid of FAKexhibit impaired migration and have large peripheral focal adhesionstructures, while cells lacking the three ubiquitous Src family membersSrc, Fyn, and Yes also demonstrate altered distribution of focaladhesions and impaired cell migration. Src kinase activity is clearlynecessary for focal adhesion turnover and cell motility, presumably bytyrosine phosphorylation of key focal adhesion substrates, such as FAK.The extracellular regulated kinase (ERK)/mitogen-activated proteinkinase (MAPK) pathway is also important in regulating focal adhesiondynamics during cell motility and it is likely that ERK/MAPK contributesto Src-induced focal adhesion turnover. Further, Westhoff et al. haverecently reported that ERK/MAPK, which is recruited to focal adhesionsfollowing v-Src activation, is required for maximal activity of theprotease calpain 2 promoting focal adhesion turnover and migration ofv-Src-transformed cells. ERK/MAPK-induced activation of calpain 2 isalso required for epidermal growth factor-induced substrate deadhesionand cell motility. Six major tyrosine phospho-acceptor sites have beenidentified on Fak, at positions 397, 407, 576, 577, 861, and 925. Tyr397 becomes phosphorylated (presumed by auto-phosphorylation) uponintegrin engagement. This leads to the formation of a consensus bindingsite for the Src SH2 domain, promoting association between Src and FAK.Phosphorylation of the remaining tyrosine residues on Fak is consideredto be Src-dependent. Westhoff et al., generated a FAK mutant (4-9F-Fak)in which each of the putative Src-induced tyrosine phosphorylation sites(Tyr 407, 576, 577, 861, and 925) has been mutated to a phenylalanine(Phe). They found that v-Src-induced phosphorylation of FAK on tyrosineresidues is necessary to enhance the adaptor function of Fak with regardto assembly of the calpain 2/FAK/p42ERK complex. Src-inducedphosphorylation of Fak is also required for Fak to undergo proteolyticcleavage by calpain in v-Src-transformed cells and is necessary forcalpain-mediated focal adhesion turnover during transformation and cellmigration. In addition, they show that Src-induced phosphorylation ofFak also regulates F-actin assembly and cell spreading. We furtherdemonstrate a role for Src-induced tyrosine phosphorylation of Fak insurvival and anchorage-independent growth of transformed cells (Westhoffet al., Molecular and Cellular Biology, 2004, 24: 8113-8133).

Fak inhibitors may be useful in treating cancer, including colon andbreast cancers, melanoma, ductal carcinoma in situ, oesophageal squamouscell carcinoma, anaplastic astrocytoma and glioblastoma, and humanhepatocellular and prostate carcinomas, as well as in reducing tumormetastasis. They may also be used in combination with otherchemotherapeutic drugs to provide synergistic effects in treatingcancers such as melanoma.

FGFR kinase family: The FGFRs (i.e., Fibroblast Growth Factor Receptors)comprise a family of related but individually distinct tyrosine kinasereceptors. They have a similar protein structure, with 3immunoglobulin-like domains in the extracellular region, a singlemembrane spanning segment, and a cytoplasmic tyrosine kinase domain. Thefibroblast growth factor receptors that have been identified are FGFR1,FGFR2, FGFR3, which is mutant in achondroplasia; and FGFR4. Sequenceanalysis of the 4.5-kb human FGFR2 gene shows an open reading frameencoding the typical membrane-spanning, tyrosine kinase receptorstructure of the FGFR gene family. A discussion of FGFR1, FGFR2, FGFR3,and FGFR4 follows.

FGFR

FGFR1: Target FGFR1 (i.e., Fibroblast Growth Factor Receptor 1) is a91.9 kDa transmembrane tyrosine kinase encoded by chromosome 8p11.2p11.1(symbol: FGFR1). FGFR1 is also known as FMS-like tyrosine kinase 2(i.e., Flt2). FGFR1 is implicated in a variety of cancers (e.g. 8p11syndrome, Braun & Shannon, Cancer Cell 2004, 5:203). Additionally, FGFR1is an important mediator of tumor angiogenesis (Compagii et al., CancerRes. 2000, 60:7163). The X-ray crystallographic structure of FGFR1 boundto fibroblast growth factor 2 has been reported by Plotnikov et al (Cell1999, 98: 641-650). Rossi et al report an FGFR1 P252R mutation infamilies affected by Pfeiffer syndrome (Rossi et al., Clin Dysmorphol.2003, 12(4):269-74). FGFR1 inhibitors may be useful in treating 8p11myeloproliferative syndrome.

FGFR2: Target FGFR2 (i.e., Fibroblast Growth Factor Receptor 2) is a 92kDa transmembrane tyrosine kinase encoded by chromosome 10q26 (symbol:FGFR2). According to OMIM, from a human tumor cDNA library, Houssaint etal. (Proc. Nat. Acad. Sci. 1990, 87: 8180-8184) isolated a gene encodinga putative receptor-like protein-tyrosine kinase that they called TK14.The amino acid sequence was closely related to that of the mouse proteinbek (bacterially expressed kinase), and more distantly related to thesequences of a chicken basic fibroblast growth factor receptor (73%sequence homology) and its presumed human equivalent, the FLG protein.Overexpression of the TK14 protein by transfection of COS-1 cells led tothe appearance of new cell-surface binding sites for both acidic andbasic fibroblast growth factors (OMIM MIM Number: 176943: Apr. 6, 2006).

Sequence analysis of the 4.5-kbp human FGFR2 gene shows an open readingframe encoding the typical membrane-spanning, tyrosine kinase receptorstructure of the FGFR gene family. Two alternative gene products havebeen characterized: KGFR and BEK. These two isoforms are identicalexcept for a 49-amino acid sequence spanning the second half of thethird Ig loop in the extracellular region. This local diversity is dueto the presence of alternative exons within FGFR2, exon B beingexpressed in the BEK product and exon K26 in KGFR. Control of thesealternative splice sites is thought to involve transacting factors(Gilbert et al., Molec. Cell. Biol. 1993, 13: 5461-5468). The variationin expressed gene product is highly significant because theligand-binding characteristics of KGFR and BEK are quite distinct.Furthermore, they have different patterns of expression in murineembryogenesis. Whereas KGFR appears to have a role in skin development,BEK is preferentially expressed in osteogenesis. BEK transcripts areconcentrated in the frontal bones, maxilla, mandibula, and ossiclecs ofthe middle ear.

To elucidate the structural determinants governing specificity in FGFsignaling, Plotnikov et al. (Cell 2000, 101: 413-424) determined thecrystal structures of FGF1 and FGF2 complexed with theimmunoglobulin-like ligand-binding domains 2 and 3 (D2 and D3) of FGFR1and FGFR2, respectively. They found that highly conserved FGF-D2 andFGF-linker (between D2 and D3) interfaces define a general binding sitefor all FGF-FGFR complexes. Specificity is achieved through interactionsbetween the N-terminal and central regions of FGFs and 2 loop regions inD3 that are subject to alternative splicing. These structures provide amolecular basis for FGF1 as a universal FGFR ligand and for modulationof FGF-FGFR specificity through primary sequence variations andalternative splicing (OMIM MIM Number: 176943: Apr. 6, 2006).

Defects in FGFR2 are a cause of Crouzon Syndrome (CS); also calledcraniofacial dysostosis type I (CFD1). CS is an autosomal dominantsyndrome characterized by craniosynostosis (premature fusion of theskull sutures), hypertelorism, exophthalmos and external strabismus,parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relativemandibular prognathism (OMIM MIM Number: #123500: May 4, 2000).

Further, defects in FGFR2 are a cause of Jackson-Weiss syndrome (JWS).JWS is an autosomal dominant craniosynostosis syndrome characterized bycraniofacial abnormalities and abnormality of the feet including broadgreat toes with medial deviation and tarsal-metatarsal coalescence (OMIMMIM Number: 176943: Apr. 6, 2006).

Further, defects in FGFR2 are a cause of Apert Syndrome, also known asacrocephalo-syndactyly type I (ACS1), which is characterized bycraniosynostosis (premature fusion of the skull sutures) and severesyndactyly (cutaneous and bony fusion of the digits), and is autosomaldominant.

Further, defects in FGFR2 are a cause of Pfeiffer Syndrome (PS), alsoknown as acrocephalosyndactyly type V (ACS5), which is characterized bycraniosynostosis with deviation and enlargement of the thumbs and greattoes, brachymesophalangy, with phalangeal ankylosis and a varying degreeof soft tissue syndactyl). Three subtypes of PS have been described:mild autosomal dominant form (type 1); cloverleaf skull, elbowankylosis, early death, sporadic (type 2); craniosynostosis, earlydemise, sporadic (type 3).

Further, defects in FGFR2 are the cause of beare-stevenson cutis gyratasyndrome (BSCGS) which is an autosomal dominant condition characterizedby the furrowed skin disorder of cutis gyrata, acanthosis nigricans,craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilicaland anogenital abnormalities and early death (OMIM MIM Number: 176943:Apr. 6, 2006).

Further, defects in FGFR2 are the cause of Antley-Bixler syndrome whichis characterized by trapezoidocephaly, midface hypoplasia, humeroradialsynostosis, bowing of femora, fractures and other abnormalities (OMIMMIM Number: #207410: Nov. 29, 2005). FGFR2 inhibitors may be useful intreating Crouzon Syndrome, Jackson-Weiss Syndrome, Apert Syndrome,craniosynostosis, Pfeiffer Syndrome, acrocephalo syndactyly type V, andBeare-Stevenson Cutis Gyrata Syndrome.

FGFR3: Target kinase FGFR3 (i.e., Fibroblast Growth Factor Receptor 3)is a 87.7 kDa transmembrane tyrosine kinase encoded by chromosome 4p16.3(symbol: FGFR3). As a member of the fibroblast growth factor family,FGFR3 is involved in a variety of activities, including mitogenesis,angiogenesis, and wound healing. Furthermore, FGFR3 plays a role in thedevelopment and maintenance of bone and brain tissue. FGFR3 regulatesbone growth by limiting the formation of bone from cartilage,particularly in the long bones. In addition, FGFR3 is activated bytranslocation in approximately 15% of multiple myeloma (Trudel, S.,Blood 2004, 103:3521). FGFR3 inhibitors may be useful in treatingangiogenesis disorders, wounds, achondroplasia, Muenke craniosynostosis,Crouzon syndrome, acanthosis nigricans, thanatophoric dysplasia, bladdercarcinomas, and multiple myeloma.

FGFR4: Target kinase FGFR4 (i.e., Fibroblast Growth Factor Receptor 4)is a 88.0 kDa transmembrane tyrosine kinase encoded by chromosome 5q35.3(symbol: FGFR4). According to OMIM, Partanen et al. (EMBO J. 1991, 10:1347-1354) reported the cDNA cloning and analysis of a novel member ofthe fibroblast growth factor receptor (FGFR) gene family expressed inK562 erythroleukemia cells. Its deduced amino acid sequence was 55%identical with the previously characterized FGFRs, FLG (FGFR1) and BEK,and had the structural characteristics of an FGFR family memberincluding 3 immunoglobulin-like domains in its extracellular part. Theexpression pattern of FGFR4 was found to be distinct from that of FLGand BEK and also distinct from that of FGFR3, which had also cloned fromK562 erythroleukemia cells. To elucidate further the physiologicrelevance of protein-tyrosine kinases and to search for additionalmembers of the gene family as possible factors in carcinogenesis,Holtrich et al. (Proc. Nat. Acad. Sci. 1991, 88: 10411-10415) amplifiedmRNA from lung tissue by the polymerase chain reaction (PCR) usingPTK-specific primers followed by sequencing of the clones. Theyidentified a novel protein-tyrosine kinase, which they called TKF(tyrosine kinase related to fibroblast growth factor receptor). Among awide variety of cells and tissues tested, including human lymphocytesand macrophages, TKF was found to be expressed only in lung and in sometumors of lung origin as well as in malignancies not derived from lungtissues. Sequence comparison has demonstrated that TKF is identical toFGFR4 (OMIM MIM Number: 134935: May 3, 2002).

The FGFR4 protein interacts with specific growth factors to conductsignals from the environment outside the cell to the nucleus. Animalstudies indicate that the FGFR4 gene is involved in muscle developmentand the maturation of bone cells in the skull. FGFR4 may also play arole in the development and maintenance of specialized cells (calledfoveal cones) in the light-sensitive layer (retina) at the back of theeye. Aberrant expression of FGFR4 is correlated with cancer of thebreast, ovary, endometrium, and fallopian tube, and with leiomyosarcomaFGFR4 inhibitors may be useful in treating cancer of the breast, lung,colon, medullary thyroid, pancreas, ovary, prostate, endometrium, andfallopian tube, head and neck squamous cell carcinomas andleiomyosarcoma.

Flt1: Target kinase Flt1 (i.e., Fins like tyrosine kinase 1) is a 150.7kDa transmembrane tyrosine kinase encoded by chromosome 13q12 (symbol:FLT1), also known as VEGFR1 (i.e., Vascular Endothelial Growth FactorReceptor 1). According to OMIM, oncogene FLT belongs to the SRC genefamily and is related to oncogene ROS. Like other members of thisfamily, it shows tyrosine protein kinase activity that is important forthe control of cell proliferation and differentiation via interactionwith PLC-gammas, PTPN11, GRB2, CRK, NCK1 and other proteins. The name isdue to the resemblance of the sequence structure of the FLT gene to thatof the FMS gene. VEGF and its high-affinity binding receptors, thetyrosine kinases Flk1 and Flt1, are thought to be important for thedevelopment of embryonic vasculature. Studying transgenic mice in whomthe Flk1 gene was disrupted, Shalaby et al. (Nature 1995, 376: 62-65)demonstrated a total failure of embryonic mice to develop blood vesselsand failure of blood island formation in the yolk sac. Fong et al.(Nature 1995, 376: 65-69) reported that in mice Flt1 is essential forthe organization of embryonic vasculature, but is not essential forendothelial cell differentiation. Transgenic mouse embryos homozygousfor a targeted mutation in the Flt1 locus formed endothelial cells inboth embryonic and extraembryonic regions, but assembled these cellsinto abnormal vascular channels and died in utero at mid-somite stages.At earlier stages, the blood islands of homozygous mice were abnormal,with angioblasts in the interior as well as on the periphery. Fong etal. (ibid.) suggested that the Flt1 signaling pathway may regulatenormal endothelial cell-cell or cell-matrix interactions during vasculardevelopment (OMIM MIM Number: 165070: Mar. 27, 2006). Flt 1 inhibitorsmay be useful in treating non-small cell lung carcinoma, prostatecarcinoma, and colorectal cancer.

Flt3: Target kinase Flt3 (i.e., Fms-like tyrosine kinase 3) is atransmembrane tyrosine kinase of 112.8 kDa encoded by chromosome 13q12(symbol: FLT3). According to OMIM, Rosnet et al. (Genomics 1991, 9:380-385) isolated a novel member of the class 3 receptors discussedabove. They demonstrated that this gene of the tyrosine kinase family,called FLT3, has strong sequence similarities with other members of thegroup. Lymphohematopoietic stem cells serve as a reservoir for virtuallyall blood cells but make up only approximately 0.01% of human or murinemarrow cells. The ability to isolate and expand this population hasclinical applications in bone marrow transplantations for cancer andgenetic diseases. Small et al. (Proc. Nat. Acad. Sci. 1994, 91: 459-463)cloned the cDNA for stem cell tyrosine kinase 1, the human homolog ofmurine Flk2/Flt3, from a CD34+ hematopoietic stem cell-enriched library.The cDNA encoded a protein of 993 amino acids with 85% identity and 92%similarity to the murine homolog. STK1, which is identical to FLT3, is amember of the type III receptor tyrosine kinase family that includesKIT, FMS, and platelet-derived growth factor receptor. STK1 expressionin human blood and marrow is restricted to CD34+ cells, a populationgreatly enriched by stem/progenitor cells. Antisense oligonucleotidesdirected against STK1 sequences inhibited hematopoietic colonyformation, most strongly in long-term bone marrow cultures. The datasuggested that STK1 may function as a growth factor receptor onhematopoietic stem and/or progenitor cells (OMIM MIM Number: 136351:Mar. 3, 2005).

Levis et al., state that Internal tandem duplication (ITD) mutations ofthe receptor tyrosine kinase FLT3 have been found in 20% to 30% ofpatients with acute myeloid leukemia (AML). These mutationsconstitutively activate the receptor and appear to be associated with apoor prognosis. In their study, dose-response cytotoxic assays wereperformed with AG1295, a tyrosine kinase inhibitor active against FLT3,on primary blasts from patients with AML, and they found that AG1295 wasspecifically cytotoxic to AML blasts harboring FLT3/ITD mutations. Theysuggest that these mutations contribute to the leukemic process and thatthe FLT3 receptor represents a therapeutic target in AML (Levis et al.,Blood 2001, 98:885-887). Flt3 inhibitors may be useful in treating acutemyeloid leukemia, myelodysplastic syndrome, acute lymphoblasticleukemia.

Flt4: Target kinase Flt4 (i.e., Fms-like tyrosine kinase 4) is atransmembrane tyrosine kinase of 145.6 kDa encoded by chromosome 5q35.3(symbol: FLT4). Flt4 is also known as VEGFR3 (i.e., Vascular EndothelialGrowth Factor Receptor 3). According to OMIM, by screening a placentacDNA library with a mouse Flt3 probe, Galland et al. (Genomics 1992, 13:475-478) isolated a human gene encoding a putative receptor-typetyrosine kinase, FLT4. The deduced amino acid sequence of theintracellular portion of the molecule showed that it was stronglyrelated to FLT1 and KDR and to a lesser degree to members of the class 3receptor-type tyrosine kinases: FMS, PDGFR, KIT, and FLT3. Primarylymphoedema, a rare, autosomal dominant disorder that leads to adisabling and disfiguring swelling of the extremities and, whenuntreated, tends to worsen with time, has been linked to the FLT4 locus(Karkkainen et al., Nat. Genet. 2000, 25: 153-9). All disease-associatedalleles analyzed had missense mutations and encoded proteins with aninactive tyrosine kinase, preventing downstream gene activation (OMIMMIM Number: 136352: Nov. 19, 2003). Flt4 inhibitors may be useful intreating primary lymphoedema.

Fms: Target kinase Fms (i.e., feline McDonough sarcoma) is a member ofthe family of genes originally isolated from the Susan McDonough strainof feline sarcoma viruses. Fms is a transmembrane tyrosine kinase of108.0 kDa coded by chromosome 5q33.2-q33.3 (symbol: CSF1R). Thestructure of the transmembrane receptor Fms comprises two Ig-likedomains, a IgC2-like domain, two additional Ig-like domains, a TMdomain, and the TK domain.

Fms is the receptor for the macrophage colony-stimulating factor(M-CSF), and is crucial for the growth and differentiation of themonocyte-macrophage lineage. Upon binding of M-CSF to the extracellulardomain of Fms, the receptor dimerizes and trans-autophosphorylatescytoplasmic tyrosine residues.

M-CSF, first described by Robinson and co-workers (Blood. 1969,33:396-9), is a cytokine that controls the production, differentiation,and function of macrophages. M-CSF stimulates differentiation ofprogenitor cells to mature monocytes, and prolongs the survival ofmonocytes. Furthermore, M-CSF enhances cytotoxicity, superoxideproduction, phagocytosis, chemotaxis, and secondary cytokine productionof additional factors in monocytes and macrophages. Examples of suchadditional factors include granulocyte colony stimulating factor(G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8). M-CSFstimulates hematopoiesis, promotes differentiation and proliferation ofosteoclast progenitor cells, and has profound effects on lipidmetabolism. Furthermore, M-CSF is important in pregnancy.Physiologically, large amounts of M-CSF are produced in the placenta,and M-CSF is believed to play an essential role in trophoblastdifferentiation (Motoyoshi, Int J Hematol, 1998, 67:109-22). Theelevated serum M-CSF levels of early pregnancy may participate in theimmunologic mechanisms responsible for the maintenance of the pregnancy(Flanagan & Lader, Curr Opin Hematol. 1998, 5:181-5).

Aberrant expression and/or activation of Fms has been implicated inacute myeloid leukemia, AML (Ridge et al, Proc. Nat. Acad. Sci., 1990,87:1377-1380). Mutations at codon 301 are believed to lead to neoplastictransformation by ligand independence and constitutive tyrosine kinaseactivity of the receptor. The tyrosine residue at codon 969 has beenshown to be involved in a negative regulatory activity, which isdisrupted by amino acid substitutions. Accordingly, Fms mutations aremost prevalent (20%) in chronic myelomonocytic leukemia and AML type M4(23%), both of which are characterized by monocytic differentiation.

A condition related to AML is chronic myeloid leukemia (CML). During themyeloid blast crisis (BC) of CML, non-random additional chromosomeabnormalities occur in over 80% of patients. However, these cytogeneticchanges have been reported to precede the clinical signs of CML-BC byseveral months to years suggesting that other biological events mayparticipate in the multistep process of acute transformation of CML. Theautocrine production of growth factors has been shown to occur inseveral hematological malignancies and particularly in AML. Specchia etal [Br J Haematol. 1992 March; 80(3):310-6] have demonstrated that IL-1beta gene is expressed in almost all cases of CML in myeloid blastcrisis, and that a high proportion of cases showed constitutiveexpression of the M-CSF gene. Many of the same patients in the Specchiaet al study demonstrated simultaneous co-expression of Fms. Afterexposure of leukemic cells to phorbol myristate acetate (PMA), releaseof M-CSF protein was documented in three of five patients studied;however, no significant interleukin-3 (IL-3), granulocyte-macrophagecolony-stimulating factor (GM-CSF) or granulocyte colony-stimulatingfactor (G-CSF), was detected in these patients. This demonstrates thatdifferent patterns of growth factors secretion exist in AML and CML, andthat distinct molecular events are likely involved in the control ofleukemic proliferation.

The observation that production of M-CSF, the major macrophage growthfactor, is increased in tissues during inflammation (Le Meur et al, J.Leukocyte Biology. 2002; 72:530-537) provides a role for Fms in certaindiseases. For example, COPD is characterized by airflow limitation thatis not fully reversible. The airflow limitation is usually progressiveand associated with an abnormal inflammatory response of the lungs tonoxious particles or gases. The chronic inflammation of COPD is observedthrough the airways, parenchyma, and pulmonary vasculature. Theinflammatory cell population consists of neutrophils, macrophages, and Tlymphocytes, along with eosinophils in some patients. Macrophages arepostulated to play an orchestrating role in COPD inflammation byreleasing mediators such as TNF-a, IL-8 and LTB4, which are capable ofdamaging lung structures and/or sustaining neutrophilic inflammation.

Further, M-CSF/fms signaling is critical to osteoclast formation andsurvival of osteoclast precursors. For example, estrogen loss inmenopause results in increased M-CSF and thus increased osteoclastnumber and bone resorption which leads to increased risk of fracture andosteoporosis. Accordingly, blockage of this signal is a target for theinhibition of bone resorption (Teitelbaum, Science. 2000; 289:1504;Rohan, Science. 2000; 289:1508).

Atherosclerosis, an inflammatory disease of the vessel walls, isassociated with significant morbidity and mortality. A effect for Fmsinhibition in the treatment and prevention of atherosclerosis depends onseveral observations (Libby, Nature. 2002; 420:868-874). First,monocytes resident in the arterial intima increase expression ofscavenger receptors and internalize modified lipoproteins. The resultinglipid-laden macrophages develop into foam cells characteristic of theatherosclerotic lesion. Macrophages in atheroma secrete cytokines andgrowth factors involved in lesion progression. Additionally, macrophagesreplicate within the intima. Through Fms, M-CSF activates the transitionfrom monocyte to lipid-laden macrophage and augments expression ofscavenger receptor A. Indeed, atherosclerotic plaques over-express M-CSFwhich is critical for atherosclerotic progression. Mice deficient inM-CSF have been found to experience less severe atherosclerosis thanmice with normal M-CSF (Rajavashisth, et. al., J. Clin. Invest. 1998;101:2702-2710; Qiao, et, al., Am. J. Path. 1997; 150:1687-1699).Accordingly, inhibitors of Fms disrupt M-CSF signaling, compromisingmonocyte to macrophage foam cell progression, macrophage survival andreplication, and cytokine signaling that participates in lesionprogression.

Wegener's granulomatosis, also known as vasculitis, is characterized bygranulomatous inflammation of the blood vessels with necrosis. Thisinflammation limits blood flow to organs with consequent damage.Although the disease can involve any organ system, Wegener'sgranulomatosis mainly affects the respiratory tract (i.e., sinuses,nose, trachea, and lungs) and the kidneys. The endothelium plays acentral role in the immunopathology of several vascular disorders inmany inflammatory conditions such as Wegener's granulomatosis in whichuse of intravenous immunoglobulin (IV Ig) has been shown to bebeneficial (see e.g., Basta ct al, J Clin Invest 1994, 94:1729-1735). Ithas been reported (Xu et al, Am. J. Path., 1998; 153:1257-1266) that IVIg inhibits endothelial cell proliferation in a dose- and time-dependentmanner and down-regulates the expression of adhesion molecule mRNA(ICAM-1 and VCAM-1), chemokine mRNA (MCP-1, M-CSF, and GM-CSF), andproinflammatory cytokine mRNA (TNF-α, IL-1β, and IL-6) induced by TNF-αor IL-1β. These results may explain, at least in part, the therapeuticeffect of IV Ig in vascular and inflammatory disorders. Additionally,these results suggest that inhibition of M-CSF activity at the level ofinteraction with Fms is an efficacious treatment strategy.

The role of M-CSF and Fins in emphysema appears to involve theregulation of elastin metabolism through control of matrixmetalloproteins. M-CSF has a role in the modulation of the accumulationand function of alveolar macrophages (AMs) in vivo (Shibata et al, Blood2001, 98: pp. 2845-2852). Osteopetrotic (Op/Op) mice have no detectableM-CSF and show variable tissue-specific reductions in macrophagenumbers. Accordingly, it was hypothesized that AMs would be decreased innumber and have altered function in Op/Op mice because of the absence ofM-CSF. Shibata et al found that lung macrophages identified in lungsections were decreased in number in 20-day-old Op/Op mice but not Op/Opmice older than 4 months compared with findings in age-matchedlittermate controls. The numbers of AMs recovered by bronchoalveolarlavage (BAL) were also reduced in young but not adult Op/Op micecompared with controls. Importantly, AMs of Op/Op mice spontaneouslyrelease higher levels of matrix metalloproteinases (MMPs) than AMs ofcontrols. Consistent with an increased release of MMP, Op/Op mice haveabnormal elastin deposition and spontaneously develop emphysema in theabsence of molecular or cellular evidence of lung inflammation.Accordingly, the modulation of metalloelastase activity in macrophagesby M-CSF may control the degradation of elastin fibers in lungs or bloodvessels.

Metastatic cancer cells cause bone destruction, with associatedfracture, pain, deformation, and hypercalcemia, due to production ofosteoclasticogenic factors including M-CSF by tumor cells (Clohisy etal, Clin. Orthop. 2000, 373: 104-14). Binding of M-CSF to the Fmsproduct stimulates formation of osteoclasts and osteolytic activity(Kodama et al, J. Exp. Med. 1991, 173: 269-72: Feng et al, Endocrinology2002, 143: 4868-74). Accordingly, inhibition of osteoclast activity atthe level of Fins offers a compelling target for amelioration of bonemetastasis.

Nephritis is inflammation of the kidneys. It may be caused for exampleby a bacterial infection of the kidneys or exposure to a toxin. However,nephritis more commonly develops from an abnormal immune reaction, whichcan occur, for example, when an antibody attacks either the kidneyitself or an antigen attached to kidney cells, or when anantigen-antibody complex formed elsewhere in the body attaches to cellsin the kidney. Some types of nephritis involve infiltration of kidneytissues by white blood cells and deposits of antibodies. In other typesof nephritis, inflammation may consist of tissue swelling or scarringwithout white blood cells or antibodies. Furthermore, nephritis canoccur anywhere in the kidneys. With respect to the glomeruli,progressive damage to glomeruli causes urine production to fall andmetabolic waste products to build up in the blood. When damage toglomeruli is severe, inflammatory cells and injured glomerular cellsaccumulate, compressing the capillaries within the glomerulus andinterfering with filtration. Scarring may develop, impairing kidneyfunction and reducing urine production. In some cases, microthrombi mayform in the small blood vessels, further decreasing kidney function.Less commonly, nephritis involves the tubulointerstitial tissues; suchinflammation is called tubulointerstitial nephritis. When inflammationdamages the tubules and the tubulointerstitial tissues, the kidneys maybecome unable to concentrate urine, eliminate (excrete) metabolic wasteproducts from the body, or balance the excretion of sodium and otherelectrolytes, such as potassium. When the tubules and tubulointerstitialtissues are damaged, kidney failure often develops. Accordingly,inhibition of F is offers a target for therapeutic intervention innephritis due to the modulation of the inflammatory response comprisingthe etiology of the disease.

Lupus nephritis, i.e., renal involvement in systemic lupus erythematosus(SLE), is a common disease manifestation with a poor prognosis. At leastthree potentially overlapping, immuno-pathogenic mechanisms for lupusnephritis are supported by experimental data. First, circulating immunecomplexes consisting chiefly of DNA and anti-DNA are deposited in thekidney. Resulting complement activation and chemotaxis of neutrophilsleads to a local inflammatory process. Second, in situ formation ofantigen and antibody complexes may similarly lead to complementactivation and leucocyte mediated injury. Third, antibodies againstspecific cellular targets may produce renal injury. An additionalmechanism is observed in SLE patients with the antiphospholipid antibodysyndrome. Glomerular thrombosis can result from the hypercoaguabilitythat accompanies antibodies directed against negatively chargedphospholipid-protein complexes (e.g. biologic false positive VDRL,anticardiolipin antibodies, and lupus anticoagulant). Mesangial lupusnephritis is accompanied by normal diagnostic findings or with a milddegree of proteinuria but typically absence of hypertension or abnormalurinary sediment. Focal and diffuse proliferative lupusglomerulonephritis are often associated with the worst prognosis forrenal survival and can be accompanied by nephrotic syndrome, significanthypertension and abnormal urine sediment. Membranous lupus nephritisoften presents with proteinuria, moderate to high grade, but usuallynormal urinary sediment in the absence of hypertension. Mesangial lupusnephropathy is generally associated with an excellent prognosis, whereasproliferative lupus nephropathy, especially diffuse variant, is oftencharacterized by hypertension, red cell casts and significantdeterioration of renal function. Nephrotic syndrome in the absence ofhypertension, active urinary sediment or significant hypocomplementemiasuggest the membranous variant of lupus nephropathy. Membranousnephropathy generally is associated with a good prognosis and relativepreservation of renal function. However, in the presence of persistentnephrotic range proteinuria, membranous lupus nephropathy can, in fact,lead to loss of renal function and end stage renal disease (ESRD).Accordingly, inhibition of Fms offers a target for therapeuticintervention in lupus due to the modulation of the inflammatory responsecomprising the etiology of the disease.

Macrophage accumulation is a prominent feature in many forms ofglomerulonephritis. Local proliferation of macrophages within the kidneyhas been described in human and experimental glomerulonephritis and mayhave an important role in augmenting the inflammatory response. Isbel etal (Nephrol Dial Transplant 2001, 16: 1638-1647) examined therelationship between local macrophage proliferation and renal expressionof M-CSF. Glomerular and tubulointerstitial M-CSF expression was foundto be up-regulated in human glomerulonephritis, being most prominent inproliferative forms of disease. Because this correlates with localmacrophage proliferation, it suggests that increased renal M-CSFproduction plays an important role in regulating local macrophageproliferation in human glomerulonephritis. In a model of renalinflammation (UUO—unilateral ureteric obstruction) anti-Fms antibodytreatment reduced macrophage accumulation (Le Meur et. al., J LeukocyteBiology, 2002, 72: 530-537). Accordingly, inhibition of Fins offers atarget for therapeutic intervention in glomerulonephritis.

Insulin resistance and obesity are hallmark of type II diabetes andthere is a strong correlation exists between insulin resistance andabdominal visceral fact accumulation (Bjorntrop, Diabetes Metab. Res.Rev., 1999, 15: 427-441). Current evidence indicates that macrophagesaccumulating in adipose tissue release TNF-a and other factors thatcause adipocyte changes (hypertrophy, lipolysis, reduced insulinsensitivity) and also promote insulin resistance in surrounding tissues.Therefore, macrophage accumulation in type 2 diabetes is important fordisease progression. Accordingly, inhibition of Fms has potential inpreventing the development of insulin resistance and hyperglycemia.

Similarly, the observation that production of M-CSF, the majormacrophage growth factor, is increased in tissues during inflammationpoints out a role for Fms in diseases, such as for example inflammatorydiseases. More particularly, because elevated levels of M-CSF are foundin the disease state, modulation of the activity of Fms can amelioratedisease associated with increased levels of M-CSF.

Fms inhibitors may be useful in treating to immune disorders, includingrheumatoid arthritis, systemic lupus erythematosis (SLE). Wegener'sgranulomatosis, and transplant rejection, inflammatory diseasesincluding Chronic Obstructive Pulmonary Disease (COPD), emphysema, andatherosclerosis, metabolic disorders, including insulin resistance,hyperglycemia, and lipolysis, disorders of bone structure ormineralization, including osteoporosis, increased risk of fracture,hypercalcemia, and bone metastases, kidney diseases, including nephritis(e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis),tubular necrosis, diabetes-associated renal complications, andhypertrophy and cancers, including multiple myeloma, acute myeloidleukemia, chronic myeloid leukemia (CML), breast cancer, and ovariancancer.

Frk: Target kinase Frk (Fyn-related kinase) is a 58.5 kDa tyrosinekinase encoded by chromosome 6q21-q22.3 (symbol: FRK). The structurecomprises an SH2, an SH3 and a tyrosine kinase domain. Hosoya et al.,report the identification of a SRC-like tyrosine kinase gene, FRK(Fyn-related kinase), fused with ETV6 in a patient with acutemyelogenous leukemia carrying t(6; 12)(q21; p13). The ETV6/FRK proteinwas shown to be constitutively autophosphorylated on its tyrosineresidues. ETV6/FRK phosphorylated histones H2B and H4 in vitro to agreater extent than did FRK, suggesting it had elevated kinase activity.ETV6/FRK could transform both Ba/F3 cells and NIH3T3 cells, whichdepended on its kinase activity (Hosoya et al., Genes Chromosomes Cancer2005, 42(3):269-79). Welsh et al. concluded that FRK/RAK contributes tocytokine-induced beta-cell death, and inhibition of this kinase couldprovide means to suppress beta-cell destruction in Type I diabetes(Welsh et al., Biochem J 2004, 382(1):261-8). Frk inhibitors may beuseful in treating acute myeloid leukemia and type I diabetes.

Fyn: Target kinase Fyn (i.e., Fyn oncogene related to Src, Fgr, Yes) isa 60.6 kDa non-receptor tyrosine kinase encoded by chromosome 6q21(symbol: FYN). Fyn is involved in regulation of mast cell degranulationin a synergistic confluence of Fyn and Lyn (i.e., v-Yes-1 Yamaguchisarcoma viral related oncogene homolog) pathways at the level of proteinkinase C and calcium regulation. Fyn inhibitors may be useful intreating Alzheimer's disease, schizophrenia and in prevention ofmetastases, e.g. in melanoma and squamous cell carcinoma.

Gsk3α, Gsk3β: Target kinase Gsk3β (i.e., Glycogen synthase kinase 3beta) is a 46.8 kDa STK encoded by chromosome 3q13.3 (symbol: GSK3B).Target kinase Gsk3a (i.e., Glycogen synthase kinase 3 alpha) is a 51.0kDa STK encoded by chromosome 19q13.2 (symbol: GSK3A).Gsk3 is aproline-directed serine-threonine kinase that was initially identifiedas a phosphorylating and inactivating glycogen synthase. Two isoforms,alpha and beta, show a high degree of amino acid homology (Stambolic &Woodgett, Biochem. J. 1994, 303: 701-704). GSK3B is involved in energymetabolism, neuronal cell development, and body pattern formation (Plyteet al., Biochim. Biophys. Acta 1992, 1114: 147-162). The X-raycrystallographic structure of Gsk3 has been reported by Dajani et al.(Cell 2001, 105: 721-732). Klein & Melton (Proc. Nat. Acad. Sci. 1996,93: 8455-8459) proposed that Gsk3 is the endogenous target of lithium indiverse systems. For example, lithium potently and specifically inhibitsGsk3 activity in vitro. This suggests a mechanism whereby lithium canmimic insulin action, and lithium inhibition of the Gsk3 pathway in thebrain could explain the actions of lithium action in manic-depressiveillness in addition to its effects on development and its insulinlikeactivity.

Phiel et al., show that therapeutic concentrations of lithium, a GSK-3inhibitor, block the production of Abeta peptides by interfering withAPP cleavage at the gamma-secretase step, but do not inhibit Notchprocessing. Importantly, lithium also blocks the accumulation of Abetapeptides in the brains of mice that overproduce APP. The target oflithium in this setting is GSK-3alpha, which is required for maximalprocessing of APP. Since GSK-3 also phosphorylates tau protein, theprincipal component of neurofibrillary tangles, inhibition of GSK-3alphaoffers a new approach to reduce the formation of both amyloid plaquesand neurofibrillary tangles, two pathological hallmarks of Alzheimer'sdisease (Phiel et al., Nature 2003, 423:435-439). Eldar-Finkelman statesthat GSK-3 inhibitors might prove useful as therapeutic compounds in thetreatment of conditions associated with elevated levels of enzymeactivity, such as type 2 diabetes and Alzheimer's disease. Thepro-apoptotic feature of GSK-3 activity suggests a potential role forits inhibitors in protection against neuronal cell death, and in thetreatment of traumatic head injury and stroke. Finally, selectiveinhibitors of GSK-3 could mimic the action of mood stabilizers such aslithium and valproic acid and be used in the treatment of bipolar mooddisorders (Eldar-Finkelman, Trends Mol Med 2002, 8:126-132). Martinez etal. state that glycogen synthase kinase 3 (GSK-3) was initiallydescribed as a key enzyme involved in glycogen metabolism, but is nowknown to regulate a diverse array of cell functions. Two forms of theenzyme, GSK-3alpha and GSK-3beta, have been previously identified. Smallmolecules inhibitors of GSK-3 may, therefore, have several therapeuticuses, including the treatment of neurodegenerative diseases, diabetestype II, bipolar disorders, stroke, cancer, and chronic inflammatorydisease (Martinez et al, Med Res Rev 2002, 22(4):373-84). GSK inhibitorsmay be useful in treating CNS disorders such as Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, diabetes type II,bipolar disorders, stroke, cancer, chronic inflammatory disease,leucopenia, schizophrenia, chronic pain, neuropathic pain, and traumatichead injury.

HCK: Target kinase HCK (hemopoietic cell kinase) is a 59.5 kDa tyrosinekinase encoded by chromosome 20q1.21 (symbol: HCK). The proteinstructure comprises an SH3, and SH2 and a bipartite kinase domain. HCKinhibitors may be useful in treating chronic myelogenous leukemia andacute lymphocytic leukemia.

Her2/Erbh2: Target kinase Her2/Erbb2 (i.e., Human EGF receptor 2) is a137.9 kDa transmembrane tyrosine kinase encoded by chromosome17q11.2-q12/17q21.2 (symbol: ERBB2). According to OMIM, the ERBB2 locus17q21 is the chromosome 17 breakpoint in acute promyelocytic leukemia(APL). Amplification of ERBB2 is observed in human salivary glandadenocarcinoma (Semba et al., Proc. Nat. Acad. Sci. 1985, 82:6497-6501)and in a gastric cancer cell line (Fukushige et al., Molec. Cell. Biol.1986, 6:955-958). Overexpression of ERBB2 has been implicated in theneoplastic transformation of prostate cancer. Interleukin-6 (IL6) is acytokine that was initially recognized as a regulator of immune andinflammatory responses, but also regulates the growth of many tumorcells, including prostate cancer. Oui et al. showed that treatment of aprostate cancer cell line with IL6 induces tyrosine phosphorylation ofERBB2 and ERBB3, but not ERBB1/EGFR. ERBB2 also forms a complex with thegp130 subunit of the IL6 receptor (IL6R) in an IL6-dependent manner.This association is important because the inhibition of ERBB2 activityresults in abrogation of IL6-induced MAPK activation (Qui et al., Nature1998, 393:83-85). Thus, ERBB2 is a critical component of IL6 signalingthrough the MAP kinase pathway. Additionally, overexpression of ERBB2confers Taxol resistance in breast cancers by inhibiting p34 (CDC2)activation (Yu et al., Molec. Cell 1998, 2:581-91) (OMIM MIM Number:164870: Jan. 30, 2006). Her2/Erbb2 inhibitors may be useful in treatingprostate and breast cancer.

Her4/Erbb4: Target kinase Her4/Erbb4 (i.e., Human EGF receptor 4) is a146.8 kDa transmembrane tyrosine kinase encoded by chromosome 2q33.3-q34(symbol: ERBB4). According to OMIM, the HER4/ERBB4 gene is a member ofthe type I receptor tyrosine kinase subfamily that includes EGFR, ERBB2,and ERBB3. The gene product of ERBB4 is a receptor for NDF/heregulin,which are essential for neuronal development. Her4/Erbb-4−/− mouseembryos exhibit axonal misprojections which correlate with aberrantmigration of a subpopulation of hindbrain-derived cranial neural crestcells. Accordingly, Her4/Erbb4 signaling provides patterning informationessential for the proper migration of neural crest cells (OMIM MIMNumber: 600543: Jul. 27, 2005). Her4/Erbb4 inhibitors may be useful intreating childhood medulloblastoma.

IGF1R: Target kinase IGF1R (insulin-like growth factor 1 receptor) is a154.8 kDa receptor tyrosine kinase encoded by chromosome 15q26.1(symbol: IGF1R). Overexpressed in breast and prostate cancer, acting toenhance tumor cell survival. IGF1R inhibitors may be useful in treatingprostate cancer and hepatocellular carcinoma.

IKK beta: Target kinase IKK beta (i.e., inhibitor of nuclear factorkappa B kinase beta) is a 86.6 kDa STK encoded by chromosome 8p11.2(symbol: IKBKB). According to OMIM, IKK beta phosphorylates serineresidues of 1-kappa-B proteins which marks them for destruction via theubiquitination pathway, thereby allowing activation of the NF-kappa-Bcomplex. Activated NF-κB complex translocates into the nucleus and bindsDNA at kappa-B-binding motifs. Yin et al (Nature 396: 77-80, 1998) haveshown that the antiinflammatory properties of aspirin and salicylate aremediated in part by their specific inhibition of IKK-beta, therebypreventing activation by NF-kappa-B of genes involved in thepathogenesis of the inflammatory response. Rossi et al (403: 103-108,2000) demonstrated a novel mechanism of antiinflammatory activity thatwas based on the direct inhibition and modification of the IKK-betasubunit of IKK. Since IKK-beta is responsible for the activation ofNF-kappa-B by proinflammatory stimuli, Rossi et al. (ibid.) suggestedthat their findings explained how cyclopentenone prostaglandins functionand can be used to improve the utility of COX2 inhibitors (OMIM MIMNumber: 603258: Nov. 16, 2005).

IKKbeta inhibitors may be useful in treating leukemia of T-cells,necrosis, neoplasms, insulin resistance, and malignant neoplasms.

Irak4: Target kinase Irak4 (i.e., Interleukin 1 receptor associatedkinase 4) is a 51.5 kDa serine/threonine kinase encoded by chromosome12q12 (symbol: IRAK4). Interleukin-1 receptor associated kinases (e.g.,IRAK1) are important mediators in the signal transduction of Toll-likereceptor (TLR, e.g., TLR4) and IL1R family members are collectivelyreferred to as TIRs. Irak4 functions in this signal transductionpathway. The structure of Irak4 comprises a DEATH domain adjacent a STKdomain. The DEATH domain is a protein-protein interaction motif found incertain proteins of the apoptotic pathway.

Irak4 was originally identified as NY-REN-64, one of 65 human tumorantigens recognized by autologous antibodies from patients with renalcell carcinoma using serological analysis of recombinant cDNA expressionlibraries (SEREX). Sequence analysis of the NY-REN-64 cDNA cloneidentified in the SEREX screen revealed a novel gene encoding atranscript of 2.8 kilobases and a predicted protein of 460 amino acids(Genbank Accession AF155118) noted to bear a protein kinase motif(Scanlan et al., Int. J. Cancer, 1999, 83, 456-464). Based on itshomology to the other IL-1 receptor-associated kinases, this gene hasmore recently been placed in the IRAK family and given the name IL-1receptor-associated kinase-4.

Irak4 is required for the efficient recruitment of IRAK1 to the IL-1receptor complex following IL-1 engagement, triggering intraccllularsignaling cascades leading to transcriptional up-regulation and mRNAstabilization. Irak4 Phosphorylates Irakl. Effective Irak4 functioningis crucial for protective immunity against specific bacteria, includingpyogenic bacterial, but is redundant against other microorganism.

Irak4 inhibitors may be useful in treating immunodeficiency syndrome,Crohn's disease, ulcerative colitis, asthma, chronic bronchitis, cardiohypertrophy, and kidney hypertension.

Itk: Target kinase Itk (i.e., IL-2 inducible T-cell kinase) is atyrosine kinase of 71.8 kDa encoded by chromosome 5q31-q32 (symbol:ITK). Itk is a T-cell specific homology of kinase Btk. The EMT Teefamily kinases are non-receptor type protein-tyrosine kinase that arehighly expressed in many hematopoietic cell lines. The TEC-familyprotein tyrosine kinases ITK, RLK(TXK) and TEC have been identified askey components of T-cell-receptor signalling that contribute to theregulation of phospholipase C-gamma, the mobilization of Ca2+ and theactivation of mitogen-activated protein kinases. Recent data also showthat TEC kinases contribute to T-cell-receptor-driven actinreorganization and cell polarization, which are required for productiveT-cell activation. Functional studies have implicated TEC kinases asimportant mediators of pathways that control the differentiation of CD4+T helper cells (Schwartzberg et al., 2005, Nature immunology, 5:284).

T cells express three TEC kinases, ITK, RLK and TEC, all of which areactivated downstream of the T-cell receptor (TCR) (Berg, L. J et al.,Annu. Rev. Immunol., 2005, 23:549) and have been shown to be involved insignaling through the TCR (Schaeffer, E. M. et al., 1999, Science,284:638). Although ITK, RLK and TEC are all found in T cells, they areexpressed at different levels and by different subpopulations. (Lucas,J. A et al., 2003, Immunol. Rev., 191:119. Colgan, J. et al. 2004,Immunity, 21:189). High expression of TEC was seen in each of 3 patientsexamined with myelodysplastic syndrome(Sato K et al., 1994, Leukemia,8:1663). Although no human disease has been associated with mutations ofthe TEC kinases that are expressed by T cells, ITK-deficient mice havespecific defects in T Helper 2 (TH2)-cell responses and reducedpathology in models of allergic asthma (Fowell et al. 1999, Immunity,11:399). Specific ITK inhibitors reduce disease in a mouse model ofallergic asthma 19, TEC kinases are activated through phosphorylation bySRC-family kinases, such as LCK, and recruitment to the plasma membranethrough binding of PtdIns(3,4,5)P3, where they are brought intoTCRsignalling complexes through interactions with SLP76, LAT and othermolecules (Bunnell, S. C. et al. 2000, J. Biol. Chem., 275:2219.).

Consistent with a role for ITK in allergic responses, increased ITKexpression has been seen in peripheralblood T cells from humans withatopic dennatitis(Matsumoto, Y. et al., 2002, Int. Arch. AllergyImmunol. 129:327). Importantly, Itk −/− mice cannot mount effectiveTH2-cell responses to infection with many pathogens that are used toevaluate TH2-cell differentiation, including Nippostrongylusbrasiliensis, Schistosoma mansoni and Leishmania major (Fowell, D. J. etal. 1999, Immunity, 11:399. Schaeffer, E. et al. 2001, Nature Immunol,2:1183).

TH2-cell responses have been implicated in the pathology of allergicasthma, which is characterized by an increased number of TH2 cells inthe lungs, increased TH2-cytokine production, increased mucus productionin the lungs and inflammation of the airways (Cohn, L et al. 2004, Annu.Rev. Immunol., 22:789). For several reasons, ITK, however, might be anideal therapeutic target for TH2-cell-mediated diseases, provided thatthe inhibitor has a high degree of specificity. Itk inhibitors may beuseful in treating allergic asthma.

Jak1: Target kinase Jak1 (i.e., Janus kinase 1) is a 132 kDa tyrosinekinase encoded by chromosome 1p31.3 (symbol: JAK1). Jak1 inhibitors maybe useful in treating Hepatitis C virus infection.

Jak2: Target kinase Jak2 (i.e., Janus kinase 2) is a 130.7 kDa tyrosinekinase encoded by chromosome 9p24 (symbol: JAK2). Jak2 inhibitors may beuseful in treating myeloproliferative disorders such as polycythaemiavera, myelofibrosis, essential thrombocythemia, myeloid metaplasia andleukemias, including acute lymphoblastic leukemia, chronic neutrophilicleukemia, juvenile myelomonocytic leukemia, CMML, Philadelphiachromosome-negative CML, megakaryocytic leukemia, and acute erythroidleukemia

Jak3: Target kinase Jak3 (i.e., Janus kinase 3) is a 125.1 kDa tyrosinekinase encoded by chromosome 19p13.1 (symbol: JAK3). According to OMIM,JAK3 is a member of the Janus kinase (JAK) family of tyrosine kinasesinvolved in cytokine receptor-mediated intracellular signaltransduction. Interleukin-2 (IL2) signaling requires the dimerization ofIL2 receptor-beta (IL2RB) with the common gamma chain (gamma-c; IL2RG).Mutations in the IL2RG gene cause X-linked severe combinedimmunodeficiency. Interleukins IL2, IL4, IL7, IL9, and IL15, whosereceptors are known to contain the common gamma chain, induce thetyrosine phosphorylation and activation of Jak3. Truncations of gamma-cand a point mutation of gamma-c, causing moderate X-linked combinedimmunodeficiency, decrease the association between the common gammachain and Jak3. Since mutations in the IL2RG gene in at least some XSCIDand XCID patients prevent normal Jak3 activation, mutations in Jak3 mayresult in an XSCID-like phenotype (OMIM MIM Number: 600173: Apr. 4,2006). A related kinase, Jak2, is activated through mutation in patientswith a variety of myeloproliferative disorders (Kralovics R. et al. NEngl J. Med. 2005 352:1779-90). The role of Jak3 in B and T lymphocytematuration and T cell function makes Jak3 a target for treatingtransplant rejection and autoimmune diseases. Jak3 inhibitors may beuseful in treating X-linked severe combined immunodeficiency,myeloproliferative disorders, transplant rejection and autoimmunediseases such as rheumatoid arthritis, inflammatory bowel syndrome,Crohn's disease, systemic lupus erythematosis, ulcerative colitis,psoriasis and multiple sclerosis.

Jnk1: Target JnkI (i.e., c-Jun kinase 1) is a 48.3 kDa serine/threoninekinase encoded by chromosome 10q11.22 (symbol: MAPKS), also known asmitogen-activated protein kinase S. Jnk1 is a mitogen-activated proteinkinase (i.e., MAPK) which form a family of serine-threonine proteinkinases that participate in a major signaling system by which cellstransduce extracellular stimuli into intracellular responses. MAPKscomprise the extracellular regulated kinases, or ERKs, for example Erk2,and the stress-activated protein kinases (SAPKs). MAPKs respond toactivation by environmental stress and pro-inflammatory cytokines byphosphorylating a number of transcription factors, primarily componentsof AP-1 such as c-Jun and ATF2 and thus regulates AP-1 transcriptionalactivity. In T-cells, Jnk1 and Jnk2 are required for polarizeddifferentiation of T-helper cells into Th1 cells. Jnk1 is activated bythreonine and tyrosine phosphorylation by either of two dual specificitykinases, MAP2K4 and MAP2K7 and inhibited by dual specificityphosphatases, such as DUSP1. Jnk1 inhibitors may be useful in treatingtype 1 diabetes, type 2 diabetes, metabolic syndrome, obesity andhepatic steatosis.

Jnk2: Target kinase Jnk2 (i.e., c-Jun kinase 2) is 48.1 kDaserine/threonine kinase encoded by chromosome 5q35 (symbol: MAPK9).According to OMIM, the transcriptional activity of the c-Junprotooncoprotein is augmented through phosphorylation at two sites byc-Jun kinases (JNKs). Using in-gel kinase assays, Hibi et al. (1993)identified 2 JNKs, 46 and 55 kD in size. The 46-kD protein Jnk1 wasshown to be a member of the mitogen-activated protein kinase (MAPK)family. Using a JNK1 cDNA as a probe, Kallunki et al. (1994) and Slusset al. (1994) isolated cDNAs encoding the 55-kD protein, which bothdesignated Jnk2. Kallunki et al. (1994) reported that the sequence ofthe predicted 424-amino acid JNK2 protein is 83% identical to that ofJNK1. Both JNKs contain a thr-pro-tyr phosphorylation motif. Northernblot analysis revealed that JNK2 is expressed as multiple transcripts inmany cell types (OMIM MIM Number: 602896: Jul. 7, 2005).

Jnk2 responds to activation by environmental stress and pro-inflammatorycytokines by phosphorylating a number of transcription factors,primarily components of AP-1 such as c-Jun and ATF2 and thus regulatesAP-1 transcriptional activity. In T-cells, JNK1 and JNK2 are requiredfor polarized differentiation of T-helper cells into Th1 cells. Jnk2isoforms display different binding patterns: alpha-1 and alpha-2preferentially bind to c-Jun, whereas beta-1 and beta-2 bind to ATF2.However, there is no correlation between binding and phosphorylation,which is achieved at about the same efficiency by all isoforms. Jnk2 isactivated by threonine and tyrosine phosphorylation by either of twodual specificity kinases, MAP2K4 and MAP2K7. Further, Jnk2 is inhibitedby dual specificity phosphatascs, such as DUSP1. Jnk2 inhibitors may beuseful in treating atherosclerosis.

Jnk3: Target kinase Jnk3 (i.e. c-Jun kinase 3) is 52.6 kDaserinc/threonine kinase encoded by chromosome 4q21-q22 (symbol: MAPK10).According to OMIM, the c-Jun kinases (JNKs) are members of themitogen-activated protein kinase (MAPK) family that activate the Juntranscription factor. Gupta et al. (EMBO J. 1996, 15: 2760-2770)isolated brain cDNAs encoding 10 different JNK isoforms, 8 of which werederived from either JNK1 or JNK2. The other 2 cDNAs were from a genethat the authors designated JNK3. JNK3 contains an extended N-terminalregion not found in JNK1 or JNK2. The 2 JNK3 isoforms, calledJNK3-alpha-1 and JNK3-alpha-2, have different C termini. By SDS-PAGE ofin vitro transcription/translation products, Gupta et al. (ibid.)determined that JNK3-alpha-1 migrates as a 45-to-48-kD doublet andJNK3-alpha-2 migrates as a 54-to-57-kD doublet. They stated that thelower band probably represents translation from a second in-frame startcodon that corresponds to the first codon in JNK1 and JNK2. All the JNKswere activated by treatment of cells with the inflammatory cytokine IL1.Multiple JNK isoforms were shown to be inactivated by MKP1. Comparisonof the binding activity of the JNK isoforms demonstrated that theydiffer in their interactions with the ATF2 (CREB2), ELK1, and Juntranscription factors. Gupta et al. (ibid.) suggested that individualJNKs selectively target specific transcription factors in vivo,providing a mechanism for the generation of tissue-specific responses tothe activation of the JNK signal transduction pathway. Mohit et al.(Neuron 1995, 14: 67-78) identified JNK3, or p49-3F12 kinase, as thegene encoding a 49-d) antigen found in the hippocampus and neocortex.The distribution of JNK3-expressing neurons closely matches that ofAlzheimer disease targeted neurons in those areas of the brain. Northernblot analysis revealed that JNK3 is expressed as a 2.7-kb mRNAexclusively in the nervous system. Mice defective for Jnk3 are resistantto excitotoxicity induced apoptosis (Yang D. D. et al., Nature 1997,389:865) (OMIM MIM Number: 602897: Mar. 13, 2006).

Jnk3 responds to activation by environmental stress and pro-inflammatorycytokines by phosphorylating a number of transcription factors,primarily components of AP-1 such as c-Jun and ATF2 and thus regulatesAP-1 transcriptional activity. Jnk3 is required for stress-inducedneuronal apoptosis and the pathogenesis of glutamate excitotoxicity.Jnk3 is activated by threonine and tyrosine phosphorylation by two dualspecificity kinases, MAP2K4 and MAP2K7. MAP2K7 phosphorylates MAPK 10 onThr-221 causing a conformational change and a large increase in Vmax.MAP2K4 then phosphorylates Tyr-223 resulting in a further increase inVmax. Jnk3 is inhibited by dual specificity phosphatases, such as DUSP1.

Jnk3 inhibitors may be useful in treating inflammatory diseasesincluding autoimmune diseases such as rheumatoid arthritis, inflammatorybowel syndrome, Crohn's disease, systemic lupus erythematosis, Sjogren'sSyndrome, psoriasis and multiple sclerosis, airway inflammatory diseasessuch as asthma, allergy, pulmonary fibrosis, and chronic obstructivepulmonary disease, and inflammation in other organs, such as CNSinflanmmation, pancreatitis, nephritis, and hepatitis; neurologicdiseases such as stroke, cerebrovascular ischemnia, andneurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, and Huntington's disease; and neoplastic diseases such asprostate tumors and myeloid leukemia.

Kdr: Target kinase Kdr (i.e., Kinase Insert Domain Receptor) is atransmembrane tyrosine kinase of 151.5 kD) a encoded by chromosome 4q12(symbol: KDR). Kdr has a complex secondary structure comprising threeIg-like (i.e., immunoglobulin-like) domains, one IGC2 (i.e.,immunoglobulin-like C2-type) domain, two additional Ig-like domains, oneadditional IGC2 domain, one TM (i.e., transmembrane) domain, and a splitTK domain, Kdr, also known as VEGFR2 (i.e., Vascular Endothelial GrowthFactor Receptor 2), Flt2, and Flkl (i.e., fetal liver kinase 1), is thereceptor for Vcgf and VegfC (i.e., Vascular endothelial growth factor C)and plays a key role in vascular development and regulation of vascularpermeability. Walter et al. (Genes Chromosomes Cancer, 2002, 33:295-303)has proposed based on an observed mutation in the kinase domain of KDRthat a potential mechanism involved in hemangioma formation is thealteration of the VEGF signaling pathway in endothelial and/or pericyticcells.

Due to the role of angiogenesis, and aberrant control thereof inpathologic states, Kdr is a target for therapeutic intervention.Angiogenesis is the process by which new blood vessel growth occurs frompre-existing vasculature and is mediated through multiple pro-angiogenicfactors, including for example Kdr. Under normal adult physiologicalconditions, angiogenesis occurs during wound healing, organregeneration, and in some aspects of female reproductive function.Angiogenesis is also important for the progression of many pathologicaldisorders such as solid tumor growth (ovarian, lung, breast,prancreatic, prostate, colon, gastrointestinal stromal tumor, non smallcell lung cancer, and epidermoid cancer), metastasis, psoriasis,rheumatoid arthritis, diabetic retinopathy and age related maculardegeneration. (Hoeben et al., 2004, Pharmacol. Rev. 56:549-580).

When the dimeric cytokine VEGF binds to the receptor tyrosine kinasesFlt-1 and/or KDR, receptor dimerization occurs, followed byautophosphorylation which leads to kinase activation and phosphorylationof intracellular substrates. This receptor tyrosine kinase activityinitiates a cellular signaling pathway which leads to endothelial cellproliferation and migration that is necessary for the process ofangiogenesis.

Tumors that grow beyond 1-2 mm in size require the process ofangiogenesis in order to receive the appropriate nutrients and oxygenthat is required for tumor progression. Accordingly, inhibition of thisprocess by small molecules that bind to the surface of receptor tyrosinekinases such as, for example, Kdr, inhibits tumor growth in both animaland human models. Direct evidence of the role of VEGF as a tumorangiogenesis factor in vivo is shown in studies in which VEGF expressionor VEGF activity was inhibited. This has been achieved with anti-VEGFantibodies, with dominant-negative VEGFR-2 mutants which inhibitedsignal transduction, and with anti-sense VEGF IRNA techniques. Allapproaches led to the reduction in tumor cell lines in vivo as a resultof inhibited tumor angiogenesis. (Scappaticci., 2002, J. Clin. Oncology20(18):3906-3927 and references within).

Kdr inhibitors may be useful in treating solid tumor growth (e.g.ovarian, lung, breast, prancreatic, prostate, colon, gastrointestinalstromal tumor, non small cell lung cancer, and epidermoid cancer),metastasis, psoriasis, rheumatoid arthritis, diabetic retinopathy andage related macular degeneration.

Kit: Target kinase Kit (i.e., feline Hardy-Zuckerman 4 sarcoma viraloncogene) is a 109.9 kDa transmembrane tyrosine kinase encoded bychromosome 4q12 (symbol: KIT). Receptor protein tyrosine kinases (RPTKs)regulate key signal transduction cascades that control cellular growthand proliferation. The Stem Cell Factor (SCF) receptor Kit is a type IIItransmembrane RPTK that includes five extracellular immunoglobulin (IG)domains, a single transmembrane domain, and a split cytoplasmic kinasedomain separated by a kinase insert segment. Kit plays an important rolein the development of melanocytes, mast, germ, and hematopoietic cells.

Stem Cell Factor (SCF) is a protein encoded by the SI locus, and hasalso been called kit ligand (KL) and mast cell growth factor (MGF),based on the biological properties used to identify it (reviewed inTsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol1997, 153:337-344; Vliagoftis, et al., Clin Immunol 1997, 100:435-440;Broudy, Blood 1997, 90:1345-1364; Pignon, Hermatol Cell Ther 1997,39:114-116; and Lyman, et al., Blood 1998, 91:1101-1134.). Herein theabbreviation SCF refers to the ligand for Kit.

SCF is synthesized as a transmembrane protein with a molecular weight of220 or 248 Dalton, depending on alternative splicing of the mRNA toencode exon 6. The larger protein can be proteolytically cleaved to forma soluble, glycosylated protein which noncovalently dimerizes. Both thesoluble and membrane-bound forms of SCF can bind to and activate Kit.For example, in the skin, SCF is predominantly expressed by fibroblasts,keratinocytes, and endothelial cells, which modulate the activity ofmclanocytes and mast cells expressing Kit. In bone, marrow stromal cellsexpress SCF and regulate hematopoiesis of Kit expressing stem cells. Inthe gastrointestinal tract, intestinal epithelial cells express SCF andaffect the interstitial cells of Cajal and intraepithelial lymphocytes.In the testis, sertoli cells and granulosa cells express SCF whichregulates spermatogenesis by interaction with Kit on germ cells.

According to OMIM, Signaling from Kit is essential for primordial germcell growth both in vivo and in vitro. Many downstream effectors of theKIT signaling pathway have been identified in other cell types, but howthese molecules control primordial germ cell survival and proliferationare unknown. Determination of the KIT effectors acting in primordialgerm cells has been hampered by the lack of effective methods tomanipulate easily gene expression in these cells, De Miguel et al.(2002) overcame this problem by testing the efficacy ofretroviral-mediated gene transfer for manipulating gene expression inmammalian germ cells. They found that primordial germ cells cansuccessfully be infected with a variety of types of retroviruses. Theyused this method to demonstrate an important role of the AKT1 inregulating primordial germ cell gro wth (OMIM MIM Number: 164920: Apr.17, 2006).

Aberrant expression and or activation of Kit has been implicated in avariety of pathologic states. For example, evidence for a contributionof Kit to neoplastic pathology includes its association with leukemiasand mast cell tumors, small cell lung cancer, testicular cancer, andsome cancers of the gastrointestinal tract and central nervous system.In addition, Kit has been implicated in playing a role in carcinogenesisof the female genital tract sarcomas of neuroectodermal origin, andSchwann cell neoplasia associated with neurofibromatosis. It was foundthat mast cells are involved in modifying the tumor microenvironment andenhancing tumor growth (Yang et al., J Clin Invest. 2003, 112:1851-1861;Viskochil, J Clin Invest. 2003, 112:1791-1793).

Kit inhibitors may be useful in treating malignancies, including mastcell tumors, small cell lung cancer, testicular cancer, gastrointestinalstromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma,carcinomas of the female genital tract, sarcomas of neuroectodermalorigin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasiaassociated with neurofibromatosis, acute myelocytic leukemia, acutelymphocytic leukemia, chronic myelogenous leukemia, mastocytosis,melanoma, and canine mast cell tumors, and inflammatory diseases,including asthma, rheumatoid arthritis, allergic rhinitis, multiplesclerosis, inflammatory bowel syndrome, transplant rejection, andhypereosinophilia.

LCK: Target kinase MCK (i.e., lymphocvte-specific protein tyrosinekinase) is a 57.9 kDa membrane associated non receptor tyrosine kinaseencoded by chromosome 1p34.3 (symbol: LCK). The protein structurecomprises an SH3 and SH2 domain. LCK inhibitors may be useful intreating acute lymphoblastic leukemia, T-cell lymphoma, lymphopenia,renal carcinoma, colon carcinoma, severe combined immunodeficiency,multiple sclerosis, inflammatory bowel and type I diabetes.

MAP2K1: Target kinase MAP2K1 (i.e., Mitogen-activated protein kinasekinase 1) is a threonine/tyrosine kinase of 43.3 kDa encoded bychromosome 15q22.1-q22.33 (symbol: MAP2K1). According to OMIM, MAP2K1 isalso known as MEK1 (i.e., MAPKERK Kinase 1). Mitogen-activated protein(MAP) kinases, also known as extracellular signal-regulated kinases(ERKs) are thought to act as an integration point for multiplebiochemical signals because they are activated by a wide variety ofextracellular signals, are rapidly phosphorylated on threonine andtyrosine residues, and are highly conserved in evolution (Crews et al.,Science 1992 258: 478-480). MAP2K1 is a critical protein kinase lyingupstream of MAP kinase which stimulates the enzymatic activity of MAPkinase Crews et al, (ibid.) found that Mek1 (i.e., MAP2K1) expressed inbacteria phosphorylates the Erk gene product in vitro. They showed thatthe Mek1 gene is highly expressed in murine brain, Seger et al. (J.Biol. Chem., 1992, 267: 25628-25631) cloned a cDNA encoding the humanhomolog of Mek1, symbolized MKK1 by them, from a human T-cell cDNAlibrary. When overexpressed in COS cells, the predicted 43,439-Daprotein led to increased phorbol ester-stimulated MAP kinase kinaseactivity. They also isolated a related cDNA, called MKK1b, that appearsto be an alternatively spliced form of MKK1. Seger et al. (ibid.)detected a 2.6-kb MKK1 transcript by Northern blot analysis in alltissues examined. Zheng and Guan (J. Biol. Chem., 1993, 268:11435-11439) also cloned a human cDNA corresponding to MEK1. They notedthat the 393-amino acid protein shares 99% amino acid identity withmurine Mek1 and 80% homology with human MEK2. The authors characterizedbiochemically the human MEK1 and MEK2 gene products. The gene is alsosymbolized MAP2K1, or PRKMK1. MAP2K1 catalyzes the concomitantphosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyrsequence located in MAP kinases and activates ERK1 and ERK2 MAP kinases.Certain inhibitors of MEK1 are potent anti-cancer agents(Sebolt-Leopold, J. S., et al., Nat. Med. 1999, 5:810) (OMIM MIM Number:176872: Jun. 6, 2005). MAP2K1 inhibitors may be useful in treating acutemyeloid leukemia, breast, ovarian and liver cancer.

MAP2K2: Target kinase MAP2K2 (i.e., Mitogen-activated protein kinasekinase 2) is a threonine/tyrosine kinase of 44.4 kDa encoded bychromosome 7q32 (symbol: MAP2K2); MAP2K2 is also known as Mek2; seeMAP2K1 above. According to OMIM, Zheng and Guan (ibid.) isolated andsequenced 2 human cDNAs encoding members of the MAP kinase kinase(MAP2K) family, designated MEK1 and MEK2 by them. The MEK2 cDNA encodesa predicted 400-amino acid protein that shares 80% sequence identitywith human MEK1. Zheng and Guan (ibid.) showed that recombinant MEK2 andMEK1 both could activate human Erk1 in vitro. They further characterizedbiochemically both MAP2K2 (OMIM MIM Number: 601263: Oct. 23, 2003).

The mitogen-activated protein kinase (MAPK) pathway is a major pathwayin the cellular signal transduction cascade from growth factors to thecell nucleus. The pathway involves kinases at two levels: MAP kinasekinases (MAPKK), and their substrates MAP (mitogen activated protein)kinases (MAPK). There are different isoforms in the MAP kinase family.[For review, see Seger, R.; Krebs, E. G. FASEB, 9, 726, (1995)]. Thecompounds of this invention can inhibit the action of one or both ofthese kinases: MEK, a MAP kinase kinase, and its substrate ERK, a MAPkinase. ERK (extracellular regulated kinases), a p42 MAPK, is found tobe essential for cell proliferation and differentiation. Overexpressionand/or over activation of MEK or ERK has been found to be associatedwith various human cancers [For example, Sivaraman, V. S. et al., C. C.J. Clin. Invest., 99, 1478 (1997)]. It has been demonstrated thatinhibition of MEK prevents activation of ERK and subsequent activationof ERK substrates in cells, resulting in inhibition of cell growthstimulation and reversal of the phenotype of ras-transformed cells[Dudley, D. T. et al., Proc. Nat. Acad. Sci., 92, 7686 (1995)]. MAP2K2inhibitors may be useful in treating cancer and inflammation.

MAP4K4: Target kinase MAP4K4 (i.e., Mitogen-activated protein kinasekinase 4) is a serine threonine kinase of 152.1 kDa encoded bychromosome 2q11.2 (symbol: MAP4K4) and is also known as HGK. MAP4K4inhibitors may be useful in treating cancer, tumor metastasis, diabetesand metabolic syndrome.

MAPKAPK2: Target kinase MAPKAPK2 (i.e., Mitogen activated protein kinaseactivated protein kinase 2) is 45.6 kDa serine/threonine kinase encodedby chromosome 1q32 (symbol: MAPKAPK2). According to OMIM, Stokoe et al.(Biochem. J. 1993, 296:843-849) described a protein kinase, which theydesignated MAPKAP kinase-2, that was active only after phosphorylationby mitogen-activated protein kinase (MAP kinase). They identifiedseveral features that distinguish MAPKAP kinase-2 from the MAPKAPkinase-1 family. Stokoe et al. (ibid.) stated that MAPKAP kinase-2 wasidentified based on its in vitro phosphorylation of glycogen synthase;however, its phosphorylation of glycogen synthase had not been shown invivo. Stokoe et al. (ibid.) cloned a partial human MAPKAP kinase-2 cDNAfrom a teratocarcinoma cell line cDNA library. The cDNA sequencerevealed the following features (in 5-prime to 3-prime order): aproline-rich region containing 2 putative SH3-binding sites, a kinasecatalytic domain, a threonine residue phosphorylated by MAP kinase, anda nuclear localization signal. By Northern analysis, Stokoe et al.(ibid.) demonstrated that the gene is expressed as a 3.3-kb transcriptin all of the 6 human tissues tested. The physiological substrate ofMAPKAP kinase 2 appears to be the small heat shock protein (HSP27/HSP25)(OMIM MIM Number: 602006: Mar. 3, 2005).

In vitro, MAPKAP kinase 2 can phosphorylate glycogen synthase at Ser-7and tyrosine hydroxylase (on Ser-19 and Ser-40). This kinasephosphorylates Ser in the peptide sequence, Hyd-X—R—X(2)-S, where Hyd isa large hydrophobic residue. MAPKAP kinase 2 is activated by twodistinct pathways: the first involves the stimulation of p42/p44 MAPK bygrowth factors, and the second, triggered by stress and heat shock,depends on the activation of MPK2 and upstream MAPKK/MAPKKK. MAPKAPK2inhibitors may be useful in treating cancer (e.g. prostate, breast),stroke, meningitis, and inflammatory disorders.

Met: Target kinase Met (i.e., Hepatocyte growth factor receptor) is155.5 kDa transmembrane tyrosine kinase encoded by chromosome 7q31(symbol: MET). According to OMIM, Cooper et al. (Nature 1984, 311:29-33) cloned a transforming gene from a chemically transformed humanosteosarcoma-derived cell line and mapped it to 7p11.4-qter Identity toall previously known oncogenes except ERBB was ruled out by the factthat they are encoded by other chromosomes; identity to ERBB is probablyexcluded by failure of direct hybridizations of the 2 probes. MET wasthe designation suggested by Cooper et al. (ibid.). Dean et al. (Nature1985, 318: 385-388) showed that MET is in the tyrosine kinase family ofoncogenes. It appeared to be most closely related in sequence to thehuman insulin receptor and ABL oncogene. From the sequence of MET cDNA,Park et al. (Proc. Nat. Acad. Sci. 1987, 84: 6379-6383) concluded thatthis oncogene is a cell-surface receptor for a then unknown ligand. Thecellular MET protooncogene product is a receptor-like tyrosine kinasecomprised of disulfide-linked subunits of 50 kD (alpha) and 145 kD(beta). In the fully processed Met product, the alpha subunit isextracellular, and the beta subunit has extracellular, transmembrane,and tyrosine kinase domains as well as sites of tyrosine phosphorylation(OMIM MIM Number: 164860: Oct. 18, 2005). Met inhibitors may be usefulin treating a variety of neoplasms including kidney, breast, bladder,non-small-cell lung, colorectal, and bladder cancers, and inhepatocellular carcinoma.

MLK1: Target kinase MLK1 (i.e., mixed-lineage kinase 1, akamitogen-activated protein kinase kinase kinase 9) is a 121.9 kDaserine/threonine kinase encoded by chromosome 14q24.3-q31 (symbol:MAP3K9). MLK1 is expressed in epithelial tumor cell lines of colon,breast and esophageal origin. Silva et al. review the mixed lineagekinase (MLK)-c-jun N-terminal kinase (JNK) signaling cascade, whichleads to the phosphorylation and activation of the transcription factorc-jun. There is much evidence, from in vitro and in vivo studies, thatthis cascade can mediate cell death. In addition, there is evidence thatit is operative upstream in the death process. It is possible thatabrogation of this pathway may forestall death before irreversiblecellular injury. They review the evidence that inhibition of the MLKscan prevent dopamine neuron cell death and the degeneration of theiraxons (Silva et al., Mov Disord 2005, 20(6):653-64). Lund et al. statethat MLK inhibitor CEP-1347 blocks the activation of the c-Jun/JNKapoptotic pathway in neurons exposed to various stressors and attenuatesneurodegeneration in animal models of Parkinson's disease (PD).Microglial activation may involve kinase pathways controlled by MLKs andmight contribute to the pathology of neurodegenerative diseases. Theyexplored the possibility that CEP-1347 modulates the microglialinflammatory response [tumour necrosis factor-alpha (TNF-alpha),interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1)] andreport that the MLK inhibitor CEP-1347 reduced cytokine production inprimary cultures of human and murine microglia, and inmonocyte/macrophage-derived cell lines, stimulated with variousendotoxins or the plaque forming peptide Abeta1-40. Moreover, CEP-1347inhibited brain TNF production induced by intracerebroventricularinjection of lipopolysaccharide in mice. As expected from a MLKinhibitor, CEP-1347 acted upstream of p38 and c-Jun activation inmicroglia by dampening the activity of both pathways. These data implyMLKs as important, yet unrecognized, modulators of microglialinflammation, and demonstrate a novel anti-inflammatory potential ofCEP-1347 (Lund et al., J Neurochem 2005, 92(6): 1439-51). MLK1inhibitors may be useful in treating neurodegenerative disorders such asAlzheimer's and Parkinson's disease and inflammatory disorders.

Mnk1: Target kinase Mnk1 (i.e., MAP kinase interacting serine/threoninekinase 1) is a 51.3 kDa STK encoded by chromosome 1p34.1 (symbol:MKNK1). According to OMIM, Fukunaga and Hunter (EMBO J. 1997,16:1921-1933) observed that the C-terminal region of Mnk1 wasphosphorylated and activated in vivo and in vitro by Erk1 and p38 MAPkinases, but not by JNK/SAPK. Waskiewiez et al., (EMBO J. 1997,16:1909-1920) reported that in vitro, Mnk1 rapidly phosphorylates eIF4Eat the physiologically relevant site, ser209. In cells, they observedthat Mnk1 is posttranslationally modified and enzymatically activated inresponse to mitogenic and stress stimuli. This activation could beblocked by inhibitors of MAP kinase kinase-1 and p38, and Waskiewiez etal. (ibid.) concluded that Mnk1 is downstream of multiple MAP kinases(OMIM MIM Number: 606724: Feb. 27, 2002).

Accordingly, dephosphorylation of eIF4E strongly correlates withinhibition or impairment of cap-dependent mRNA translation under certainstress conditions such as heat shock, nutrient deprivation, oxidative orosmotic stress, and infection of mammalian cells with certain virusessuch as adenovirus (Ad) or influenza virus, among others. Mnk1inhibitors may be useful in treating conditions associated with heatshock, nutrient deprivation, oxidative or osmotic stress, infection ofmammalian cells (e.g. with viruses such as adenovirus (Ad) or influenzavirus), and autoimmune diseases.

p38: Target kinase p38 (i.e., Mitogen-activated Protein Kinase 14) is a41.5 kDa STK encoded by chromosome 6p21.3-p21.2 (symbol: MAPK14).According to OMIM, production of interleukin-1 and tumor necrosis factor(TNF) from stimulated human monocytes is inhibited by a series ofpyridinyl-imidazole compounds called CSAIDs (cytokine-suppressiveantiinflammatory drugs). These agents have shown activity in a varietyof animal models of acute and chronic inflammation. Using radiolabeledchemical probes for radioligand binding assays and photoaffinitylabeling experiments, Lee et al. (Nature 1994, 372:739-746) identified,purified, cDNA-cloned, and biochemically characterized 2 CSBPs(CSAID-binding proteins) as molecular targets of pyridinyl-imidazolecytokine inhibitors. They designated the 2 closely relatedmitogen-activated protein kinases (MAPKs) CSBP1 and CSBP2. Binding ofpyridinyl-imidazole compounds inhibited CSBP kinase activity and wasdirectly correlated with their ability to inhibit cytokine production,suggesting that the CSBPs are critical for cytokine production. Lee etal. (ibid.) considered the 2 to be products of alternative splicing. The4.2-kb CSBP mRNA encodes a predicted 360-amino acid protein and wasexpressed in all tissues tested. CSBP1 and CSBP2 are identical exceptfor a 75-nucleotide stretch within the coding region. Han et al.(Science 1994, 265: 808-811) cloned the mouse homolog as a protein thatis tyrosine phosphorylated as part of the protein kinase cascadesinduced by endotoxic lipopolysaccharide. They named this 38-kD proteinp38. As p38 is a member of the stress-activated protein kinase (SAPK)class of MAPKs, Goedert et al. (Genomics 1997, 41:501-502) referred tothis protein as SAPK2A. Zervos et al. (Proc. Nat. Acad. Sci. 1995,92:10531-10534) identified p38 as a human protein that interacts withMAX protein and designated it MXI2. The MXI2 gene encodes a 297-residueprotein whose sequence indicates that it is related to the extracellularsignal-regulated kinases (ERK protein kinases). MXI2 in yeast interactswith Max and with the C terminus of c-Myc. MXI2 phosphorylates MAX bothin vitro and in vivo. The authors speculated that phosphorylation byMXI2 may effect the ability of MAX to oligomerize with itself and itspartners, bind DNA, or regulate gene expression (OMIM MLM Number:600289: Feb. 13, 2006).

There are four known isoforms of p38, i.e., p38-α, p38β, p38γ, and p38δ.The α and β isoforms are expressed in inflammatory cells and are keymediators of TNF-α production. Inhibiting the p38α and β enzymes incells results in reduced levels of TNF-α expression. Also, administeringp38α and β inhibitors in animal models of inflammatory disease hasproven that such inhibitors are effective in treating those diseases.Accordingly, the p38 enzymes serve an important role in inflammatoryprocesses mediated by IL-1 and TNF-α. Compounds that reportedly inhibitp38 kinase and cytokines such as IL-1 and TNF-α for use in treatinginflammatory diseases are disclosed in the following publishedinternational patent applications: WO 00/12497 (quinazoline derivativesas p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidinederivatives for the same purpose); WO 00/12497 (discusses therelationship between p38 kinase inhibitors); and WO 00/12074 (piperazineand piperidine compounds useful as p38 inhibitors).

p38 responds to activation by environmental stress, pro-inflammatorycytokines and lipopolysaccharide (LPS) by phosphorylating a number oftranscription factors, such as ELK1 and ATF2 and several downstreamkinases, such as MAPKAPK2 and MAPKAPK5. Additionally, p38 plays acritical role in the production of some cytokines, for example IL-6. p38phosphorylates ELK1 and ATF2.

p38 is activated by threonine and tyrosine phosphorylation by either oftwo dual specificity kinases, MAP2K3 or MAP2K6, and potentially alsoMAP2K4 and it is inhibited by dual specificity phosphatases, such asDUSP1. p38 is specifically inhibited by the binding ofpyridinyl-imidazole compounds, which are cytokine-suppressiveanti-inflammatory drugs (CSAID).

p38 inhibitors have the potential to treat a number of diseases,including, but not limited to acute coronary syndrome, stroke,atherosclerosis, and inflammatory diseases such as rheumatoid arthritis,inflammatory bowel disease, and Crohn's disease.

PDGFR kinase family: Related to Fms and Kit are two platelet-derivedgrowth factor receptors, alpha (i.e., PDGFRA) and beta (PDGFRB). Thegene coding for PDGFRA is located on chromosome 4q12 in the same regionof chromosome 4 as the oncogene coding for Kit. Most gastrointestinalstromal tumors (GIST) have activating mutations in Kit, and mostpatients with GISTs respond well to Gleevec, which inhibits Kit.Heinrich et al. (Science 2003, 299:708-10.) have shown thatapproximately 35% of GISTs lacking Kit mutations have intragenicactivation mutations in the gene encoding pdgfra, and that tumorsexpressing Kit or PDGFRA were indistinguishable with respect toactivation of downstream signaling intermediates and cytogenetic changesassociated with tumor progression. Thus, Kit and PDGFRA mutations appearto be alternative and mutually exclusive oncogenic mechanisms in GISTs.PDGF is a potent growth factor and chemoattractant for smooth musclecells (SMCs), and the renarrowing of coronary arteries followingangioplasty is due in part to the enhanced proliferation of SMCs inresponse to increased levels of PDGF. Therefore, compounds that inhibitthe kinase activity of PDGFr may be useful in the treatment ofrestenosis. In addition, since PDGF and PDGFr are overexpressed inseveral types of human gliomas, small molecules capable of suppressingPDGFr activity have potential utility as anticancer therapeutics[Nister, M., J. Biol. Chem., 266, 16755 (1991); Strawn, L. M., J. Biol.Chem. 269, 21215 (1994)].

PDGFRα: Target PDGFRα (i.e., Plate Derived Growth Factor Receptor,alpha) is a 122.7 kDa transmembrane tyrosine kinate encoded bychromosome 4q12 (symbol: PDGFRA). According to OMIM, The KIT oncogene,another member of the PDGF growth factor receptor subfamily, is locatedin the same region of chromosome 4 (Stenman et al., Genes ChromosomesCancer 1989, 1:155-158). PDGFR1 (i.e. PDGFRB) and CSF1R (i.e. FMS) arealso membrane-spanning growth factor receptors with tyrosine kinaseactivity. The PDGFR1 and CSF1R genes appear to have evolved from acommon ancestral gene by gene duplication, inasmuch as these 2 genes aretandemly linked on chromosome 5 (Roberts et al., Cell 1988, 55:655-661). They are oriented head-to-tail with the 5-prime exon of FMSlocated only 500 bp from the last 3-prime exon of PDGFRB. An analogoussituation may exist for the PDGFR2 (i.e. PDGFRA) and KIT genes onchromosome 4. From an evolutionary point of view, it is possible thatthe distribution of these 4 loci, PDGFR2, KIT, PDGFR1, and FMS, onchromosomes 4 and 5 is a result of gene duplication and chromosomedoubling (tetraploidization) (OMIM MIM Number: 173490: Mar. 21, 2005).PDGFRA inhibitors may be useful in treating idiopathic hypereosinophilicsyndrome, chronic eosinophilic leukemia, glioma, gastrointestinalstromal tumors (GISTs), juvenile myelomonocytic leukemia, metastaticmedulloblastoma, atherogenesis, and restenosis.

PDGFRβ: Target PDGFRβ (i.e., Plate Derived Growth Factor Receptor, beta)is a 124.0 kDa transmembrane tyrosine kinate encoded by chromosome5q31-q32 (symbol: PDGFR1). According to OMIM, stimulation of cellproliferation of the receptor for PDGF has been implicated inatherogenesis and in cell transformation by the SIS oncogene. Escobedoet al. (1986) sequenced the receptor and cloned its gene. Gronwald etal. (Proc. Nat. Acad. Sci. 1988, 85:3435-3439) cloned a cDNA coding forhuman PDGFR and studied its expression. The cDNA contained an openreading frame that coded for a protein of 1,106 amino acids. Intransfectants, Gronwald et al. (ibid.) found that the PDGFR cloneexpressed a high affinity receptor specific for the BB isoform of PDGF,i.e., PDGF dimers composed of 2 B chains. There may be a separate classof PDGF receptor that binds both the homodimers and the heterodimer.Claesson-Welsh et al. (Molec. Cell, Biol. 1988, 8:3476-3486) determinedthe structure of the human PDGF receptor as deduced from a full-lengthcDNA clone. The receptor expressed in Chinese hamster ovary cells wasfound to bind specifically to B-chain-containing PDGF molecules. Withthe description of a second PDGF receptor, it is necessary to use thesymbol PDGFR1. Matsui et al. (1989) designated the second type of PDGFRas type alpha because PDGF binding was blocked by AA as well as BBisoforms of the ligand; the product of the earlier cloned PDGF receptorwas termed type beta (OMIM MIM Number: 173410: Nov. 19, 2003).

PDGFRβ has been implicated in hematological cancers, such as chronicmyelomonocytic leukemia (CMML), in which a significant number ofpatients have a t(5; 12) (q33; p13) translocation resulting inTEL-PDGFRβ fusion protein. Golub et al. report that the consequence ofthe t(5; 12) translocation is expression of a fusion transcript in whichthe tyrosine kinase domain of the platelet-derived growth factorreceptor beta (PDGFRβ) on chromosome 5 is coupled to a novel ets-likegene, tel, on chromosome 12. The tel-PDGFR beta fusion demonstrates theoncogenic potential of PDGFRβ and may provide a paradigm for earlyevents in the pathogenesis of AML (Golub et al., Cell 1994, 77:307-316).PDGFRB inhibitors may be useful in treating idiopathic hypereosinophilicsyndrome, chronic eosinophilic leukemia, juvenile myelomonocyticleukemia, and metastatic medulloblastoma.

PDPK1: Target PDPK1 (3-phosphoinositide dependent protein kinase-1) is a63.2 kDa serine/threonine kinase encoded by chromosome 16p13.3 (symbol:PDPK1). PDPK1 inhibitors may be useful in treating cancers and diabetes.

Pim1: Target Pim1 (i.e., Proviral Integration Site 1) is a 35.7 kDaserine/threoninc kinase encoded by chromosome 6p21.2 (symbol: PIMI)found in the cytoplasm and nucleus. The structure of Pim1 comprises aSTK (i.e., serine/threonine kinase) domain. X-ray crystal structures ofPim1 bound to various small molecules have recently been solved (Jacobs,et al., J Biol Chem 2005 280: 13728-34; Qian, et al., J Biol Chem 2005280: 6130-7; Kumar, et al., J Mol Biol 2005 348: 183-93).

Pim1 is the first described member of a unique family of serinethreonine kinases, which includes at least two other kinases (PIM2 andPIM3) with significant sequence homology to Pim1 (van der Lugt, et al.,Embo J 1995 14: 2536-44; Feldman, et al., J Biol Chem 1998 273:16535-43). The PIM1 protooncogene was originally identified as a geneticlocus frequently activated by the proviral insertion of Moloney murineleukemia virus into mouse T cell lymphomas (Cuypers et al., Cell 1984,37:141-150). Several substrates of Pim1 phosphorylation have beenidentified, including c-Myb (Winn, et al., Cell Cycle 2003 2: 258-62),BAD (Yan, et al., J Biol Chem 2003 278: 45358-67; Aho, et al., FEBS Lett2004 571: 43-9), SOCS-1 (Chen, et al., Proc Natl Acad Sci USA 2002 99:2175 80), Cdc25A (Mochizuki, et al., J Biol Chem 1999 274: 18659-66),HP1 (Koike, et al., FEBS Lett 2000 467: 17-21). PAP-1 (Maita, et al.,Eur J Biochem 2000 267: 5168-78), p21^(cip1/waf1) (Wang, et al. BiochimBiophys Acta 2002 1593: 45-55), PTP-U2S (Wang, et al., Arch BiochemBiophys 2001 390: 9-18), and NFATc1 (Rainio, et al., J Immunol 2002 168:1524-7). Pim1 has been shown to have diverse biological roles in cellsurvival, proliferation, differentiation, and immune response (Wang, etal, J Vet Sci 2001 2: 167-79; Bachmann, et al., Int J Biochem Cell Biol2005 37: 726-30). However, mice lacking all three Pim genes haverecently been shown to be viable and demonstrate that the PIM kinasesare important for growth factor signaling, but are not essential fordevelopment (Mikkers, et al., Mol Cell Biol 2004 24: 6104-15). Duringembryonal development PIM genes are expressed in partially overlappingfashion in cells in both immune and central nervous system as well as inepithelia (Eichmann A, Yuan L, Breant C, Alitalo K, and Koskinen P J.(2000) Developmental expression of PIM kinases suggests functions alsooutside of the hematopoietic system. Oncogene 19: 1215-1224). PIM-1, theprototypical member of the PIM family is located both in the cytoplasmand nucleus, but its precise role in these two locations has not beenfully elucidated.

Dysfunction of Pim1 has been implicated in the progression of multiplecancers, including several hematopoietic and prostate cancers. Althoughthe exact mechanisms by which Pim1 participates in cell transformationhave not been completely elucidated, several reports point to theability of Pim1 to prolong cell survival (Lilly, et al., Cancer Res 199757: 5348-55; Lilly, et al., Oncogene 1999 18: 4022-31; Moroy, et al.,Proc Natl Acad Sci USA 1993 90: 10734-8). Overexpression of Pim1 hasbeen observed in myeloid and lymphoid acute leukemia and Pim1 isconstitutively expressed in some myeloid leukemia cell lines (Lilly, etal., Oncogene 1992 7: 727-32; Amson, et al., Proc Natl Acad Sci USA 198986: 8857-61). Increased Pim1 expression has also been identified inneoplastic prostate cancer specimens from patients by cDNA microarrayanalysis and by anti-Pim1 antibody staining (Dhanasekaran, et al.,Nature 2001 412: 822-6). In a transgenic murine model of prostate cancerin which human c-myc is expressed, the gene expression profile isconsistent with that seen in human prostate cancer, includingupregulation of Pim1 (Ellwood-Yen, et al., Cancer Cell 2003 4: 223-38).In addition, Pim1 may participate in deregulated cell growth in prostatecancer through the hormone independent activation of the androgenreceptor, a typical characteristic of advanced prostate cancer thatoffers poor patient prognosis (Kim, et al., Oncogene 2004 23: 1838-44).The PIM-1 proto-oncogene has also been implicated in human hematopoieticmalignancies with its overexpression frequently detected in humanhematopoictic cell lines as well as in fresh tumor cells from patientswith leukemia (Nagarajan et al. Proc. Natl. Acad. Sci, USA, 1986,83:2556-2560; Meeker et al., Oncogene Res. 1987, 1: 87-101; Amson etal., Proc. Natl. Acad. Sci. USA, 1989, 86: 8857-8861).

In diffuse large cell lymphoma (DLCL), the most common form ofnon-Hodgkin's lymphoma, Pim1 has been shown to undergo chromosomaltranslocations, resulting in its overexpression (Akasaka, et al., CancerRes 2000 60: 2335-41). A recent study showed that Pim1 was also thetarget of an aberrant somatic hypermutation in DLCL (Pasqualucci, etal., Nature 2001 412: 341-6). Hypermutation sites are distributed inboth 5′ UTR and coding sequence, and independent of the chromosomaltranslocations. Notably, there are seven missense mutations introducedinto the coding exons of the gene. These missense mutations may affectthe three-dimensional structure and, in some cases, the kinase activityof the Pim1 protein. Hypermutations are also detected in Pim1 found inprimary central nervous system lymphomas (Montesinos-Rongen, et al.,Blood 2004 103: 1869-75) and multiple subtypes of AIDS-inducednon-Hodgkin's lymphomas (Gaidano, et al., Blood 2003 102: 1833-41).Inhibition of Pim1 kinase activity by small molecules has the potentialto offer a therapeutic benefit in these diseases.

Transgenic mice with PIM-1 driven by Emu enhancer sequences demonstratedthat PIM-1 function as a weak oncogene because by itself it does notlead to tumor formation but does so after a second oncogenic gene becomeoverexpressed. In 75% of the tumors over-expressing PIM-1, the secondgene found to be over-expressed is c-myc (van der Houvcn van Oordt C W,Schouten T G, van Krieken J H, van Dierendonck J H, van der Eb A J,Breuer M L. (1998) X-ray-induced lymphomagenesis in E mu-PIM-1transgenic mice: an investigation of the co-operating molecular events.Carcinogenesis 19:847-853). In fact when crosses were made betweenEmu-PIM transgenic mice and Emu-myc transgenic mice, the combination ofgenes is so oncogenic that the offsprings die in utero due to pre B celllymphomas (Verbeck S, van Lohuizen M, van der Valk M, Domen J, Kraal G,and Berns A. (1991) Mice bearing the Emu-myc and Emu-PIM-1 transgenesdevelop pre-B-cell leukemia prenatally. Mol. Cell. Biol., 11:1176-1179).

Mice deficient for PIM-1 show normal synaptic transmission andshort-term plasticity but failed to consolidate enduring LTP (i.e., longterm potentiation) even though PIM-2 and PIM-3 are expressed in thehippocampus (Konietzko U, Kauselmann G, Scafidi J, Staubli U, Mikkers H,Berns A, Schweizer M, Waltereit R, and Kuhl D. (1999) PIM kinaseexpression is induced by LTP stimulation and required for theconsolidation of enduring LTP. EMBO J. 18: 3359-3369).

Various factors are known to enhance the transcription of PIM-1 kinasein mouse and human. PIM-1 closely cooperates with another oncoprotein,c-myc, in triggering intracellular signals leading to bothtransformation and apoptosis and the selective inhibition of apoptoticsignaling pathways leading to Bcl-2 (van Lohuizen M, Verbeek S,Krimpenfort P, Domen J, Saris C, Radaszkiewiez T, and Berns A. (1989)Predisposition to lymphomagenesis in PIM-1 transgenic mice: cooperationwith c-myc and N-myc in murine leukemia virus-induced tumors. Cell56:673-682; Brcuer M L, Cuypers H T, Berns A. (1989). Evidence for theinvolvement of PIM-2, a new common proviral insertion site, inprogression of lymphomas. EMBO J. 8:743-748.; Verbeck S, van Lohuizen M,van der Valk M, Domen J, Kraal G C, and Berns A. (1991) Mice bearing theE mu-myc and E mu-PIM-1 transgenes develop pre-B-cell leukemiaprenatally. Mol. Cell. Biol. 11: 1176-1179; Shirogane T. Fukada T,Muller J M, Shima D T, Hibi M, and Hirano T. (1999) Synergistic rolesfor PIM-1 and c-Myc in STAT3-mediated cell cycle progression andantiapoptosis. Immunity, 11: 709-719). PIM-1 kinase is induced by T cellantigen receptor cross linking by cytokines and growth factors and bymitogens including IL2, IL3, IL6, IL9, IL12, IL5, GM-CSF, G-CSF, IFNa,INFg, prolactin, ConA, PMA and anti-CD3 antibodies (Zhu N, Ramirez L M,Lee R L, Magnuson N S, Bishop G A, and Gold MR. (2002) CD40 signaling inB cells regulates the expression of the PIM-1 kinase via the NF-kappa Bpathway. J. Immunol. 168: 744-754). PIM-1 expression is rapidly inducedafter cytokine stimulation and the proliferative response to cytokinesis impaired in cells from PIM-1 deficient mice (Domen J, van der Lugt NM, Acton D, Laird P W. Linders K, Berns A. (1993) PIM-1 levels determinethe size of early B lymphoid compartments in bone marrow. J. Exp. Med.178: 1665-1673).

Members of the PIM family of kinases interact with Socs-1 protein, apotent inhibitor of JAK activation thereby playing a major role insignaling down stream of cytokine receptors. The phosphorylation ofSocs-1 by PIM family of kinases prolongs the half-life of Socs-1protein, thus potentiating the inhibitory effect of Socs-1 on JAK-STATactivation (Chen X P, Losman J A, Cowan S, Donahue E, Fay S, Vuong B Q,Nawijn M C, Capece D, Cohan V L, Rothman P. (2002) PIM serine/threoninekinases regulate the stability of Socs-1 protein. Proc. Natl. Acad. Sci.USA 99:2175-2180.). PIM-1 is expressed during G1/S phase of the cellcycle suggesting that it is involved in cell cycle regulation (Liang H,Hittelman W, Nagarajan L., Ubiquitous expression and cell cycleregulation of the protein kinase PLM-1. (1996) Arch Biochem Biophys.330:259-265).). PIM-1 kinase activity and the protein level is increasedin CD 40 mediated B cell signaling and this increase in PIM-1 level ismediated through the activation of NF-kB (Zhu et al. 2002. supra). PIM-1can physically interact with NFATc transcription factors enhancing NFATcdependant transactivation and IL2 production in Jurkat cells (Rainio EM, Sandholm J, Koskinen P J. (2002) Cutting edge: Transcriptionalactivity of NFATc1 is enhanced by the PIM-1 kinase. J. Immunol.168:1524-1527). This indicates a novel phosphorylation dependantregulatory mechanism targeting NFATc1 through which PIM-1 acts as downstream effector of ras to facilitate IL2 dependant proliferation andsurvival of lymphoid cells (ibid.).

Pim1 is shown to interact with many other targets. Phosphorylation ofCdc25A phosphatase, a direct transcriptional target of c-myc, increaseits phosphatase activity both in-vivo and in-vitro indicating thatCdc25A link PIM-1 and c-myc in cell transformation and apoptosis(Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, and Kuchino Y.(1999) Physical and functional interactions between PIM-1 kinase andCdc25A phosphatase. Implications for the PIM-1-mediated activation ofthe c-Myec signaling pathway; J. Biol. Chem. 274:18659-18666). PIM-1also phosphorvlate PTP-U2S, a tyrosine phosphatase associated withdifferentiation and apoptosis in myeloid cells, decreasing itsphosphatase activity and hence preventing premature onset of apoptosisfollowing PMA-induced differentiation (Wang et al, (2001) Pim-1negatively regulates the activity of PTP-U2S phosphatase and influencesterminal differentiation and apoptosis of monoblastoid leukemia cells,Arch. Biochem. Biophys. 390:9-18). The phosphorylation of another PIM-1target, heterochromatin protein 1(HP1) has been shown to be involved intranscription repression (Koike et al., FEBS Lett. 2000, 467: 17-21).

Pim1 inhibitors may be useful in treating cancers such as hematopoietic(e.g. acute myeloid and acute lymphoid leukemias) and prostate cancers,and non-Hodgkin's lymphomas.

Pim2: Target kinase Pim2 (i.e., Serine/threonine-protein kinase ProviralIntegration Site 2) is a 34.2 kDa STK encoded by chromosome Xp11.23(symbol: PIM2). Pim2 has also been shown to play a role in cell survivaland the control of apoptosis and its value as an inhibitor target hasbeen considered (Yan, et al., J Biol Chem 2003 278: 45358-67; Giles,Blood 2005 105: 4158-4159; Fox, et al., Genes Dev 2003 17: 1841-54).Pim2 has been found to be overexpressed in some lymphomas (Cohen, etal., Leuk Lymphoma 2004 45: 951-5). Additionally, Pim2 is required forthe rapamycin resistant T-cell survival and the rapamycin-resistantgrowth of nontransformed hematopoietic cells (Hammerman, et al., Blood2005 105: 4477-83; Fox, et al., J Exp Med 2005 201: 259-66). Pim2inhibitors may be useful in treating lymphomas.

Pim3: Target kinase Pim3 (i.e., Serine/threonine-protein kinase ProviralIntegration Site 3) is a 35.8 kDa STK encoded by chromosome 22q13(symbol: PIM3). Pim3 has recently been shown to be overexpressed inhuman hepatocellular carcinoma cells and its ablation resulted inattenuated cell proliferation and enhanced apoptosis, suggesting thatPim3 can also participate in abnormal cell growth and inhibition ofapoptosis (Fujii, et al., Int J Cancer 2005 114: 209-18). Pim3inhibitors may be useful in treating hepatocellular carcinoma.

PKC alpha: Target kinase PKC alpha (i.e., Protein kinase C alpha) is a76.8 kDa STK encoded by chromosome 17q22-q23.2 (symbol: PRKCA). Proteinkinase C (PKC) is the major phorbol ester receptor. Nine mammalianmembers of the PKC family have been identified and designated alpha,beta, gamma, delta, epsilon, zeta, eta, theta, and lambda. According toOMIM, Parker et al. (Science 1986, 233:853-859) purified PKC from bovinebrain and through the use of oligonucleotide probes based on partialamino acid sequence, derived cDNA clones from bovine cDNA libraries.Activation of PKC by calcium ions and the second messengerdiacylglycerol is thought to play a central role in the induction ofcellular responses to a variety of ligand-receptor systems and in theregulation of cellular responsiveness to external stimuli. Birnbaum etal. (Science 2004, 306:882-884) showed that high levels of PKC activityin prefrontal cortex, as seen for example during stress exposure,markedly impaired behavioral and electrophysiologic measures of workingmemory. Birnbaum (ibid.) concluded that excessive PKC activation candisrupt prefrontal cortical regulation of behavior and thought, possiblycontributing to signs of prefrontal cortical dysfunction such asdistractibility, impaired judgment, impulsivity, and thought disorder(OMIM MIM Number: 176960: Apr. 17, 2006). A mutation in PKC-alpha(D294G) correlates with pituitary tumor. PKC alpha inhibitors may beuseful in treating pituitary tumors and prefrontal cortical dysfunctionsuch as distractibility, impaired judgment, impulsivity, and thoughtdisorder, also may be used to sensitize chemotherapy in breast, colon,and non small cell lung cancers.

PKC beta: Target kinase PKC beta (i.e., Protein kinase C, beta I) is a76.7 kDa STK encoded by chromosome 16p11.2 (symbol: PRKCB1). Accordingto OMIM, Leitges et al. (Science 1996, 273:788-791) found that micehomozygous for a targeted disruption of the PRKCB1 gene develop animmunodeficiency characterized by impaired humoral immune responses andreduced cellular responses of B cells similar to X-linkedimmunodeficiency (Xid) in mice. Thus, they concluded that the 2isoforms, PKC-beta-1 (PRKCB1) and PKC-beta-II (PRKCB2), play animportant role in B-cell activation and may be functionally linked toBruton tyrosine kinase in antigen receptor-mediated signal transduction(OMIM MIM Number: 176970: Mar. 3, 2006). In general, inhibitors PKC betaand PKC isoforms may be effective in treating disorders characterized bydysregulated NFKB survival signaling. PKC beta inhibitors may be usefulin treating diabetic retinopathy.

PKC theta: Target kinase PKC-theta (i.e., Protein kinase, theta) is a81.9 kDa STK encoded by chromosome 10p15 (symbol: PRKCQ). According toOMIM, in an attempt to find PKC isoforms that are involved in growthcontrol and/or activation of T lymphocytes, Baier et al., (J. Biol.Chem. 1993, 268:4997-5004) used a human peripheral bloodlymphocyte-derived cDNA library was employed to identify a novel PKCisoform, termed PKC-theta. The gene encodes a protein of approximately80 kD, expressed predominantly in lymphoid tissues and hematopoieticcell lines, particularly T cells. The alpha form (PRKCA) has been mappedto chromosome 17, the beta form (PRKCB1) to chromosome 16, the gammaform (PRKCG) to chromosome 19, and the delta form (PRKCD) to chromosome3. By fluorescence in situ hybridization, Erdel et al. (Genomics 1995,25:595-597) assigned the PRKCQ gene to 10p15. Blanco and Brown(Mammalian Genome 1997, 8:70-71) mapped the homolog Pkcq to mousechromosome 2 by analysis of an interspecific backcross Sun et al.(Nature 2000, 404:402-407) demonstrated that PKC-theta is essential forT-cell antigen receptor (TCR)-mediated T-cell activation but dispensableduring TCR-dependent thymocyte development. They generated micedeficient in Pkc-theta by homologous recombination, Mutant mice werenormal and fertile. TCR-initiated NF-kappa-B activation was absent fromPKC-theta −/− mature T lymphocytes, but was intact in thymocytes.Activation of NF-kappa-B by tumor necrosis factor-alpha andinterleukin-1 was unaffected in the mutant mice. Induction of JNK wasnormal in T cells from mutant mice. Sun et al. (ibid.) concluded thatPKC-theta functions in a unique pathway that links the TCR signalingcomplex to the activation of NF-kappa-B in mature T lymphocytes. Usinghyperinsulinemic-euglycemic clamps. Kim et al. (J. Clin. Invest. 2004,114:823-827) demonstrated that skeletal muscle and hepatic insulinaction did not differ between wildtype and Pkc-theta null mice. A 5-hourlipid infusion decreased insulin-stimulated skeletal muscle glucoseuptake in the wildtype mice that was associated with 40 to 50% decreasesin insulin-stimulated tyrosine phosphorylation of insulin receptorsubstrate-1 (IRS1) and IRS1-associated PI3K activity. In contrast,Pkc-theta inactivation prevented fat-induced defects in insulinsignaling and glucose transport in skeletal muscle. Kim et al. (ibid.)concluded that PKC-theta is a crucial component mediating fat-inducedinsulin resistance in skeletal muscle (OMIM MIM Number: 600448: Oct. 15,2004).

Li et al. report that PKC plays a critical role in competitiveactivity-dependent synapse modification at the neuromuscular synapse invitro and in vivo. This action involves a reduction of the strength ofinactive inputs to muscle cells that are activated by other inputs. Adecrease of postsynaptic responsiveness and a loss of postsynapticacetyl choline receptors account for the heterosynaptic loss in vitro.The loss is not seen in preparations in which PKC has been blockedpharmacologically. Here, they show that the loss does not occur in invitro preparations made from animals genetically modified to lack thetheta isoform of PKC. Synapse elimination in the newborn period in vivois delayed but is eventually expressed in knock-out animals.PKC-dependent synapse reduction is suppressed in heterologous culturescombining normal nerve and PKC-theta-deficicnt muscle, as might beexpected from the postsynaptic locus of the changes that underlie theactivity-dependent plasticity. Preparations in which PKC-theta-deficientneurons innervated normal muscle also exhibited a marked deficit inPKC-deficient synapse reduction. The presynaptic action of PKC-thetaimplied by this observation is blocked by TTX, and the authors proposethat the activity-related synapse strengthening is decreased bypresynaptic PKC-theta. Thus, PKC-theta in both presynaptic andpostsynaptic elements plays a critical role in activity-dependentsynapse modulation and loss (Li et al., Journal of Neuroscience 2004,24(15):3762-3769). PKC theta inhibitors may be useful in treatinginsulin resistance, T-cell lymphoma.

Plk1: Target kinase Plk1 (i.e., Polo like kinase 1) is a 68.3 kDa STKencoded by chromosome 16p12.3 (symbol: PLK1). Plk1 is a regulatorrequired for multiple mitotic processes, including bipolar mitoticspindle formation, actin ring formation, and chromosomal segregation.According to OMIM, Holtrich et al. (Proc. Nat. Acad. Sci. 1994,91:1736-1740) observed that PLK1 transcripts are present at high levelin tumors of various origins. In vertebrate cells, the nuclear entry ofmitosis-promoting factor (MPF) during prophase is thought to beessential for the induction and coordination of M-phase events.Phosphorylation of cyclin B1 is central to its nuclear translocation.Toyoshima-Morimoto et al. (Nature 2001, 410:215-2201 purified a proteinkinase from Xenopus M-phase extracts that phosphorylates a crucialserine residue (S147) in the middle of the nuclear export signalsequence of cyclin B1. They identified this kinase as Plx1, a Xenopushomolog of PLK1. During cell cycle progression in HeLa cells, a changein the kinase activity of endogenous Pls1 toward S147 and/or S133correlates with a kinase activity in the cell extracts. An anti-PLK1antibody depleted the M-phase extracts of the kinase activity towardS147 and/or S133. An anti-phospho-S147 antibody reacted specificallywith cyclin B1 only during G2M phase. A mutant cyclin B1 in which S133and S147 were replaced by alanines remained in the cytoplasm, whereaswildtype cyclin 131 accumulated in the nucleus during prophase. Further,coexpression of constitutively active Plk1 stimulates nuclear entry ofcyclin B1. Toyoshima-Morimoto et al. (ibid.) concluded that Plk1 may beinvolved in targeting MPF to the nucleus during prophase (OMIM MIMNumber: 602098: Aug. 5, 2005). Plk1 inhibitors may be useful in treatingcancers (e.g. lymphoma of the thyroid, non-Hodgkin's lymphomas,colorectal cancers, leukemias and melanoma), also useful as sensitizerin chemotherapy.

Pyk2: Target kinase Pyk2 (i.e., Protein-Tyrosine Kinase 2) is a 115.9kDa tyrosine kinase of the FAK family (see e.g., target Fak) encoded bychromosome 8p21.1 (symbol: PTK2B). As with target kinase Fak, Pyk2comprises B41 and TK domains, and Pyk2 is also known as Fak2 (i.e.,Focal Adhesion Kinase 2). Because Pyk2 is calcium dependent, it is alsoknown as CADAK (i.e., calcium-dependent tyrosine kinase).

As mentioned, another member of the FAK subfamily is kinase Fak. Pyk2and Fak shares 65% sequence identity in the kinase domain and havesimilar domain structure: an N-terminus domain for integrin binding, anda C-terminus domain for Paxillin binding. Fak is ubiquitously expressedwhile Pyk2 exhibits a more restricted tissue expression patternprimarily in neuronal and hematopoetic tissues.

According to OMIM, Focal adhesion kinases (i.e., FAKs) are cytoplasmicprotein-tyrosine kinases associated with focal adhesions and whoseactivity is induced by ligand binding to various receptors includingthose of, for example, integrin and growth factors. FAKs are known totarget paxillin and are substrates for Src family kinases (Calalb etal., Molec. Cell. Biol. 1995, 15:954-963). Herzog et al. (Genomics 1996,32:484-486) identified a gene for another focal adhesion kinase bylow-stringency screening of a hippocampus cDNA library. They symbolizedthe gene FAK2. The FAK2 cDNA encodes a predicted 1,009-amino acidprotein with 42% identity to FAK1. Northern blot analysis detected a4.5-kb mRNA in brain, kidney, spleen, and lymphocytes. Protein-tyrosinekinases in the central nervous system are activated in response to avariety of neurotrophic factors that control neuronal differentiationand survival via cell surface receptors. Also, protein phosphorylationis involved in membrane excitability and the function of ion channels.Lev et al. (Nature 1995, 376:737-745) discovered a nonreceptor typeprotein kinase that is highly expressed in adult rat brain. The kinase,which they symbolized PYK2 (proline-rich tyrosine kinase-2), was clonedfrom a rat spinal cord cDNA library using degenerate PCR primerscorresponding to conserved tyrosine kinase motifs of PYK1 (see Manser etal., Nature 1993, 363:364-367). Lev et al. (ibid.) cloned the humanhomolog from a human fetal brain cDNA library using the rat sequence asa probe. The predicted protein of 1,009 amino acids has 61% sequenceidentity to the FAK1 protein (Ptk2) (OMIM MLM Number: 601212: Jan. 19,2005). PKC-theta may represent an important signaling intermediatebetween neuropeptide activated receptors or neurotransmitters thatincrease calcium flux and the downstream signals that regulate neuronalactivity. PKC-theta interacts with the SH12 domain of Grb2, and mayphosphorylate the voltage-gated potassium channel protein Kv1.2. Itsactivation is highly correlated with the stimulation of c-Jun N-terminalkinase activity.

Pyk2 regulates multiple signaling events crucial for macrophagemorphology and migration. It mediates the Jak-dependent activation ofMAPK and Stat1. By rapidly translocating to the vicinity of the immunesynapse after T cell receptor stimulation, Pyk2 plays an essential rolein T cell activation and polarized secretion of cytokines. Themorphology and behavior of macrophages in Pyk2−/− mice were impaired.Macrophages isolated from mutant mice failed to become polarized, toundergo membrane ruffling, and to migrate in response to chemokinestimulation. Moreover, the contractile activity in the lamellipodia ofPyk2−/− macrophages was impaired, as revealed by measuring the rearwardmovement toward the nucleus of fibronectin-coated beads on thelamellipodia in opposition to an immobilizing force generated by opticaltweezers.

Pyk2 is implicated in several therapeutic areas including inflammation(e.g. osteoporosis, Polycystic Kidney Disease, rheumatoid arthritis andsome bowel diseases) and CNS disease like Parkinson's disease andAlzheimer's disease). Pyk2 in osteoclasts is an adhesion kinase,localized in the sealing zone, activated by ligation of v3 integrin, andphosphorylated by Src kinase. Methods for preventing cell death in asubject and their application in the treatment of neurodegenerativediseases and conditions, such as Alzheimer's disease, stroke,Parkinson's disease have been patterned by Griswold-Prenner Irene andPowell Kyle.

Pyk2 is also a potential therapeutic target for tumors. Pyk2 is a noveleffector of fibroblast growth factor receptor 3 activation. Pyk2facilitates EGFR- and c-Src-mediated Stat3 activation and has a role intriggering Stat3-induced oncogenesis. HER3, but not HER2, mediates thephosphorylation of the C-terminal region of PYK2 to promote a mitogenicresponse through activation of the MAPK pathway. Furthermore, PYK2phosphorylation by HER3 induces tumor invasion. A central role of PYK2in signaling downstream of HER3 is substantiated by the demonstrationthat expression of a dominant-negative PYK2-KM construct abrogates theHeregulin-induced MAPK activity and inhibits the invasive potential ofglioma cells.

Overexpression of wild-type RAFTK significantly enhanced breast cancercell invasion, while overexpression of the mutants Tyr402 or Tyr881 ofRAFTK inhibited this migration. Therefore, Pyk2 may serve as a mediatorand an integration point between focal adhesion molecules inHRG-mediated signaling in T47D breast cancer cells.

A murine pancreatic cancer cell line overexpressing Pyk2, mPanc02, wastreated with a Pyk2-dominant negative adenovirus (Ad-Pyk2DN), or GFP(ad-GFP) adenovirus. The dominant negative Pyk2 adenovirus is able todecrease tumor growth and increase survival in several in vivo tumormodels.

Although no point mutation of Pyk2 has been reported to be significantin any disease, human umbilical vein endothelial cells express mRNAtranscripts for both the full length isoform Pyk2 and the truncatedisoform Pyk2-H containing the C-terminal deletion.

Pyk 2 inhibitors may be useful in treating inflammation (e.g.osteoporosis, polycystic kidney disease, rheumatoid arthritis andinflammatory bowel disease), CNS disease (e.g. Parkinson's disease andAlzheimer's disease), stroke and cancers (e.g. gliomas, breast cancer,and pancreatic cancer).

Ret: Target Ret (i.e., Rearranged during Transfection) is a 124.3 kDatyrosine kinase encoded by chromosome 10q11.2 (symbol: RET). Ret is alsoknown as c-ret (i.e., cellular ret). The domain structure of Retcomprises cadherin, transmembrane, and TK domains. Cadherins areglycoproteins involved in Ca2+-mediated cell-cell adhesion; see e.g.,Yap et al., Annu Rev Cell Dev Biol. 1997; 13:119-46).

According to OMIM, the RET protooncogene is one of the receptor tyrosinekinases, cell-surface molecules that transduce signals for cell growthand differentiation. The RET gene was defined as an oncogene by aclassical transfection assay. RET can undergo oncogenic activation invivo and in vitro by cytogenetic rearrangement (Grieco et al., Cell1990, 60:557-563). Mutations in the RET gene are associated withmultiple endocrine neoplasia, type IIA (MEN2A), multiple endocrineneoplasia, type IB (MEN2B), Hirschsprung disease (HSCR; aganglionicmegacolon), and medullary thyroid carcinoma (MTC) (OMIM MIM Number:164761: Jan. 27, 2006).

Ret (Rearranged during Transformation) was identified as a rearrangedhuman oncogene in the classic NIH3T3 transformation assay (Takahashi etal., 1985, Cell 42(2):581-8) and subsequently characterized as aReceptor Tyrosine kinase (Takahashi et al., 1988, Oncogene 3(5):571-8).

Ret and NTRK1 (i.e., Neutrotrophic tyrosine receptor kinase 1) arereceptor tyrosine kinase (RTK) proteins which play a role in thedevelopment and maturation of specific components of the nervous system.Their alterations have been associated to several human diseases,including some forms of cancer and developmental abnormalities. Thesefeatures have contributed to the concept that one gene can beresponsible for more than one disease. Moreover, both genes encoding forthe two RTKs show genetic alterations that belong to either “gain offunction” or “loss of function” class of mutations. In fact, receptorrearrangements or point mutations convert Ret and NTRK1 into dominantlyacting transforming genes leading to thyroid tumors, whereasinactivating mutations, associated with Hirschsprung's disease (HSCR)and congenital insensitivity to pain with anhidrosis (CIPA), impair Retand NTRK1 functions, respectively.

Implication of Ret in human tumorigenesis was indicated by the frequentidentification of rearranged Ret sequences that transformed NIH3T3 cellsin the DNA isolated from Papillary Thyroid Carcinoma DNAs. In thesecases, the Ret gene was fused to as yet unknown PTC DNA sequences in thetumor DNA but not the normal patient DNA (Grieco et al., 1990, Cell60(4):557-63). In addition, the chromosomal mapping of Ret to chromosome10q11.2 co-localized with genetic mapping data that implicated a geneinvolved in patients with MEN2A (Multiple Endocrine Neoplasia 2A)(Ishizaka et al. 1989 Oncogene 4(12):1519-21). Expression analysis ofthe RET oncogene in a number of human tumors consistently detectedexpression of normal-sized transcripts of the RET proto-oncogene inhuman pheochromocytomas and in human medullary thyroid carcinomas, bothof familial and sporadic type (Santoro et al., 1990, Oncogene 5:1595-8).

Further analysis of the tumor DNA of patients with Multiple endocrineneoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma(FMTC) identified mutations in the RET sequence resulting in amino acidchanges in the encoded Ret protein (Donis-Keller 1993, Hum Mol. Genet.2(7):851-6). Likewise, mutations in the RET gene were correlated withHirschprung disease, a developmental disorder with genetic deletions andmutations in the chromosomal location of the RET gene (Luo et al., 1993,Hum Mol. Genet. 2(11):1803-8).

By early 1994, multiple papers describe the inactivation of the RET genein patients with Hirschsprung disease and similar phenotype in knock outmice. In addition, activating mutations in Ret are now identified inpatients with MEN2A, MEN2B, and FMTC (reviewed by van Heyningen V.,1994, Nature 367(6461):319-20).

It was determined that Ret regulates cell survival. Signal transductionmolecules that form a complex with Ret as a result of these phosphorylmoieties, such as GRB2, SOS, ras, and raf, propagate a signal in thecell that promotes neural survival. Thus, compounds that promote theinteractions of the se stimulatory molecules of Ret would enhance theactivity of c-Ret. Alternatively, protein phosphatases can remove thephosphoryl moieties placed on the intracellular region of Ret inresponse to GDNF, and thus inhibit the signaling capability c-Ret. Thus,compounds that inhibit phosphatases of Ret will probably enhance thesignaling capacity of c-Ret.

Ret is implicated in the development and survival of enteric, synaptic,and sensory neurons and neurons of the renal system upon stimulation byGDNF (Jing, et al., 1996, Cell 85:1113-1124: Trupp, et al., 1996, Nature381:785-789; Durbec, et al., 1996, Nature 381:789-793). Lack of functionmutations in Ret can lead to Hirschsprung's disease, for example, whichmanifests itself as a decrease in intestinal tract innervation inmammals. Thus, compounds that activate Ret are potential therapeuticagents for the treatment of neurodegenerative disorders, including, butnot limited to, Hirschsprung's disease, Parkinson's disease, Alzheimer'sdisease, and amyotrophic lateral sclerosis. Compounds that inhibit Retfunction can also be anti-cancer agents as over-expression of Ret incells is implicated in cancers, such as cancer of the thyroid.

Modulation of Ret activity may also be useful in treating cancers of thenerve tissue, such as neuroblastoma, even if an abnormality is not foundthe signaling pathway.

As stated above, RET gene is responsible for MEN2 syndromes, which areinherited in an autosomal dominant fashion with high penetrance anddiverse clinical manifestations. The predominant RET mutation ismissense mutation which is restricted to 9 codons (codons 609, 611, 618,620, 630, 634, 768, 804 and 918). The MEN2 syndromes have 3 subtypes:multiple endocrine neoplasia type 2A (MEN2A), MEN2B, and familialmedullary thyroid carcinoma (FMTC). Missense mutations at exon 10(codons 609, 611, 618, and 620) and exon 11 (codons 630 and 634) havebeen identified in 98% of MEN2A families and in 85% of FMTC families.Missense mutations at codons 768 and 804 have been known to beresponsible for 5.about.10% of FMTC cases. In addition, missensemutations at exon 16 (codon 918) have been found in 95% of MEN2B cases.

Ret inhibitors may be useful in treating cancer of the thyroid,neuroblastoma, familial medullary thyroid carcinoma (FMTC), multipleendocrine neoplasia type IIA and IIB (MEN2A, MEN2B), andneurodegenerative disorders (e.g. Hirschsprung's disease, Parkinson'sdisease, Alzheimer's disease, and amyotrophic lateral sclerosis)

Ron: Target kinase Ron (i.e., Ron protein tyrosine kinase) is a 152.2kDa transmembrane tyrosine kinase encoded by chromosome 3p21.3 (symbol:MST1R), also known as macrophage stimulating protein receptor (i.e., MSPreceptor). Ron, a member of the Met hepatocyte growth factor receptorfamily, was originally cloned from a human foreskin keratinocyte cDNAlibrary by Ronsin et al (Oncogene 1993, 8: 1195-1202). RON is expressedin various cell types including macrophages, epithelial andhematopoietic cells. Ron activation results in a variety of cellularresponses in vitro, such as activation of macrophages, proliferation,migration, and invasion, which suggest a broad biologic role in vivo.Hemizygous mice (Ron +/−) grow to adulthood; however, these mice arehighly susceptible to endotoxic shock and appeared to be compromised intheir ability to downregulate nitric oxide production. Accordingly, Ronplays a role in early mouse development and may play a limited role inthe inflammatory response. Further, Ron may be involved in cancerdevelopment and progression (OMIM MIM Number: 600168: Jan. 20, 2006).Ron inhibitors may be useful in treating cancer and inflammation.

ROCK (ROCK1 and ROCK2): Target kinase ROCK1 (i.e., Rho-associated,coiled-coil containing protein kinase 1) is a 158.2 kDa serine/threoninekinase encoded by chromosome 18q11.1 (symbol: ROCK1). Target kinaseROCK2 (i.e., Rho-associated, coiled-coil containing protein kinase 2) isa 160.9 kDa serine/threonine kinase encoded by chromosome 2p24 (symbol:ROCK2). ROCK inhibitors may be useful in treating related to cancers(e.g. ovarian cancer, hepatocellular carcinoma, pancreatic cancer),ocular disease (e.g. glaucoma), cardiac hypertrophy, improved renalperfusion, transplant rejection, and acute respiratory distresssyndrome.

Src: Target kinase Src (i.e., v-Src Avian Sarcoma Schmidt-Ruppin A-2viral oncogene) is a 59.8 kDa non-receptor tyrosine kinase encoded bychromosome 20q12-q13 (symbol: SRC). The structure of Src comprises SH3and SH2 domains adjacent to the TK domain. According to OMIM, Azarnia etal. (Science 1988, 239:398-401) found that overexpression of the SRCgene in NIH 3T3 cells caused reduction of cell-to-cell transmission ofmolecules in the 400- to 700-dalton range. Downregulation was enhancedby point mutation of tyrosine-527, whereas mutation of tyrosine-416suppressed both the downregulation of communication by the tyr-527mutation and that by gene overexpression. The regulation ofcommunication by SRC may be important in the control of embryonicdevelopment and cellular growth. Luttrell et al. (Science 1999,283:655-661) demonstrated that c-src binds to the amino terminus ofbeta-arrestin-1 in a complex resulting from the stimulation of beta-2adrenergic receptors. Activated beta-2-adrenergic receptor boundbeta-arrestin-1, which then bound c-sre. This interaction targeted thecomplex to clathrin-coated pits and allowed for beta-2-adrenergicactivation of the MAP kinases Erk1 and Erk2. TRANCE, a TNF familymember, and its receptor, RP K, are critical regulators of dendriticcell and osteoclast function. Wong et al. (Molec. Cell 1999,4:1041-1049) demonstrated that TRANCE activates the antiapoptoticserineithreonine kinase PKB (AKT1) through a signaling complex involvingSRC and TRAF6. A deficiency in SRC or addition of SRC family kinaseinhibitors blocked TRANCE-mediated PKB activation in osteoclasts. SRCand TRAF6 interacted with each other and with RANK upon receptorengagement. TRAF6, in turn, enhanced the kinase activity of SRC, leadingto tyrosine phosphorylation of downstream signaling molecules such asCBL. These results defined a mechanism by which TRANCE activates SRCfamily kinases and PKB, and provided evidence of cross-talk between TRAFproteins and SRC family kinases. Using a colon cancer cell line,Avizienyte et al. (Nature Cell Biol. 2002, 4:632-638) studied the roleof SRC in cell adhesion and metastasis. Transfection and overexpressionof a constitutively active SRC mutant reduced cell-cell contacts andcaused redistribution of adherens junction components to discreteadhesion-like structures at the tips of membrane protrusions. Expressionof active SRC also impaired the movement of E-cadherin from the cellinterior to the plasma membrane following exposure to high calcium.Avizienyte et al. (ibid.) provided evidence that the alpha-V and beta-1integrins and FAK were required for the adhesion changes induced by SRC.Sandilands et al. (Dev. Cell 2004, 7:855-869) found that RhoBcolocalized with active Src in the cytoplasm of mouse embryonicfibroblasts, and they presented evidence that RhoB is a component of‘outside-in’ signaling pathways that coordinate Src activation withtranslocation to transmembrane receptors (OMIM MIM Number: 190090: Jan.7, 2005).

The Src family of cytoplasmic protein tyrosine kinases consists of atleast eight members (Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) thatparticipate in a variety of signaling pathways [Schwartzberg, P. L.,Oncogene, 17, 1463 (1998)]. The prototypical member of this tyrosinekinase family is p60src (Src). Src is involved in proliferation andmigration responses in many cell types. In limited studies, Src activityhas been shown to be elevated in breast, colon (90%), pancreatic (>90%)and liver (>90%) tumors. Greatly increased Src activity is alsoassociated with metastasis (>90%) and poor prognosis. Antisense Srcmessage impedes growth of colon tumor cells in nude mice [Staley et al.,Cell Growth & Differentation, 8, 269 (1997)], suggesting that Srcinhibitors should slow tumor growth. In addition to its role in cellproliferation, Src also acts in stress response pathways, including thehypoxia response. Previous studies have shown that colonic tumor cellsgenetically engineered to express antisense Src message form tumorsdemonstrating reduced vascularization in nude mouse models [Ellis, etal., J. Biol. Chem., 273, 1052 (1998)], suggesting that Src inhibitorswould be anti-angiogenic as well as anti-proliferative.

Apart from its role in cancer, Src also appears to play a role inosteoporosis. Mice genetically engineered to be deficient in srcproduction were found to exhibit osteopetrosis, the failure to resorbbone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin. Invest.,90, 1622 (1992)]. This defect was characterized by a lack of osteoclastactivity. Since osteoclasts normally express high levels of Src,inhibition of Src kinase activity may be useful in the treatment ofosteoporosis [Missbach, M., Bone, 24, 437 (1999)]. Src inhibitors may beuseful in treating cancer and osteoporosis.

Stk6: Target Stk6 (i.e., Serine/Threonine protein kinase 6) is a 45.8kDa serine/threonine kinase encoded by chromosome 20q13.2-q13.3 (symbol:STK6). According to OMIM, Kimura et al. (J. Biol. Chem. 1997,272:13766-13771) cloned a cDNA encoding a novel human serine/threoninekinase, STK6, that has high homology with the Aurora and Ip11 kinases.Mutations in these yeast kinases are known to cause abnormal spindleformation and missegregation of chromosomes. Northern and Western blotanalyses revealed a high level of STK6 expression product in testis andproliferating culture cells such as HeLa cells. The endogenous levels ofSTK6 protein and protein kinase activity were tightly regulated duringcell cycle progression in HeLa cells. The protein was upregulated duringG2/M and rapidly reduced after mitosis. Immunofluorescence studiesrevealed specific localization of STK6 protein to the spindle poleregion during mitosis. The results suggested that STK6, like Aurora andIpl1, is involved in cell growth and/or chromosome segregation (OMIM MIMNumber: 602687: Apr. 1, 2003).

Aurora A belongs to the family of STKs that are involved in mitoticevents such as centrosome separation and chromosome segregation and aretherefore essential for cell proliferation (Bischoff & Plowman, TrendsCell Biol. 1999, 9:454-459); Giet & Prigent, 1999, Cell Science 112:3591-3601). Inhibitors of the Aurora kinase family therefore have thepotential to block growth of all tumors.

The three identified Aurora kinases of this family are known undervarious names: Aurora-A (Aurora 1), Aurora B (Aurora 2) and Aurora C(Aurora 3). Alternate names for Aurora A, described here further areserine/threonine protein kinase 15 (STK 15), BTAK Aurora-related kinase1 (ARK1). The mouse homolog of Aurora A, STK6 also referred to as AIK,is highly homologous to STK15. All Aurora kinase family members arehighly homologous proteins responsible for mitotic events such ascentrosome maturation and segregation, chromosome segregation, mitoticspindle function and cytokinesis. Peak expression of Aurora occursduring the G2 and mitotic phase in cycling cells and then decreases andremains low or undetectable in resting cells (Shindo et al., 1998,Biochem. Biophys. Res. Commun. 244: 285-292). In mammalian cellsproposed substrates for Aurora include histone H3, a protein involved inchromosome condensation, and CENP-A, myosin II regulatory light chain,protein phosphatase 1, TPX2, all of which are required for celldivision.

Zhou et al., (Zhou et al., 1998, Nature Genet. 20: 189-193) found thatAurora is involved in the induction of centrosomeduplication-distribution abnormalities and aneuploidy in mammaliancells. Centrosomes appear to maintain genomic stability through theestablishment of bipolar spindles during cell division, ensuring equalsegregation of replicated chromosomes to 2 daughter cells. Deregulatedduplication and distribution of centrosomes are implicated in chromosomesegregation abnormalities, leading to aneuploidy seen in many cancercell types. Zhou et al., (Zhou et al., 1998, Nature Genet. 20: 189-193)found amplification of Aurora A in approximately 12% of primary breasttumors, as well as in breast, ovarian, colon, prostate, neuroblastoma,and cervical cancer cell lines. Additionally, high expression of AuroraA mRNA was detected in tumor cell lines without evidence of geneamplification. Ectopic expression of Aurora A in mouse NIH 3T3 cells ledto the appearance of abnormal centrosome number (amplification) andtransformation in vitro. Finally, over-expression of Aurora A innear-diploid human breast epithelial cells revealed similar centrosomeabnormality, as well as induction of aneuploidy. These findingssuggested that Aurora A is a critical kinase-encoding gene, whoseover-expression leads to centrosome amplification, chromosomalinstability, and transformation in mammalian cells.

The AURKA gene is over expressed in many human cancers. Ectopicover-expression of aurora kinase A in mammalian cells induces centrosomeamplification, chromosome instability, and oncogenic transformation, aphenotype characteristic of loss-of-function mutations of p53. Katayamaet al. (Katayama et al., 2004, Nature Genet. 36: 55-62) showed thatAurora A kinase phosphorylates p53 at ser315, leading to itsubiquitination by MDM2 and proteolysis. P53 is not degraded in thepresence of inactive Aurora A or ubiquitination-defective MDM2.Silencing of Aurora kinase A results in less phosphorylation of p53 atser315, greater stability of p53, and cell-cycle arrest at G2-M. Cellsdepleted of Aurora kinase A are more sensitive to cisplatin-inducedapoptosis, and elevated expression of aurora kinase A abolishes thisresponse. In a sample of bladder tumors with wildtype p53, (Katayama etal., 2004, Nature Genet. 36: 55-62) found a correlation between elevatedexpression of aurora kinase A and low p53 concentration. They concludedthat Aurora A kinase is a key regulatory component of the p53 pathwayand that over-expression of Aurora A leads to increased degradation ofp53, causing down-regulation of checkpoint-response pathways andfacilitating oncogenic transformation of cells.

By immunoprecipitation of epitope-tagged proteins from transfectedHEK293 cells. Kunitoku et al. (Kunitoku et al., 2003, Dev. Cell 5:853-854) demonstrated direct interaction between the genes CENPA andAURKA. In vitro, AURKA phosphorylated CENPA on ser7, a residue that isalso phosphorylated by AURKB. Examination of the role of both kinases inthe phosphorylation of CENPA revealed that the reaction is mediatedsequentially by AURKA and AURKB in early mitosis. Mitotic cells in whichphosphorylation of CENPA on ser7 was prevented exhibited a substantialproportion of misaligned chromosomes resulting from a defect in theability of kinetochores to attach to microtubules.

By yeast 2-hybrid analysis of HeLa cells, 1Hirota et al. (Hirota et al.,2003, Cell 114: 585-598) determined that AURKA interacts with Ajuba(JUB). The two proteins interacted in mitotic cells and becamephosphorylated as they did so. In vitro analysis revealed that Ajubainduced the autophosphorylation and consequent activation of AURKA.Depletion of Ajuba prevented activation of AURKA at centrosomes in lateG2 phase and inhibited mitotic entry. Hirota et al. (Hirota et al.,2003, Cell 114: 585-598) concluded that Ajuba is an essential activatorof AURKA in mitotic commitment.

The mammalian Aurora kinase family has been implicated in tumorigenesisof a variety of different cancers. The main role of Aurora A in tumordevelopment is in controlling chromosome segregation during mitosis(Bischoff & Plowman, Trends Cell Biol, 1999, 9:454-459). Over-expressionof Aurora A transforms rodent fibroblasts (Bischoff et al., 1998, EMBOJ. 17:3052-3065). The elevated levels of Aurora A induce misregulationof chromosome segregation that results in cells containing multiplecentrosomes and multipolar spindles leading to aneuploidy, a distinctivefeature of most cancers. (Zhou et al., 1998, Nature Genet. 20: 189-193).Ewart-Toland et al. (Ewart-Toland et al., 2003, Nature Genet. 34:403-412) found that tumors from individuals carrying the 91A alleleshowed more evidence of aneuploidy than those from individuals who werehomozygous for the common 91T allele. They concluded that individualswith even one copy of the Aurora A 91A allele develop tumors that haveon average a higher degree of aneuploidy than those from individualshomozygous for 91T. The oncogenic activity of Aurora kinases is likelyto be linked to the generation of such genetic instability. Miyoshi etal. (Miyoshi et al., 2001, Int. J. Cancer 92: 370-373) and Sakakura etal. (Sakakura, et al., 2001, Br. J. Cancer 84: 824-831) report acorrelation between amplification of the Aurora A locus and chromosomalinstability in mammary and gastric tumors.

Over-expression of Aurora kinases have been reported in a wide range ofhuman tumors. Aurora A expression is elevated in tumor cell linesderived from colon, breast, lung, melanoma, kidney, ovary, pancreas,CNS, gastric tract and leukemia cells (Tatsuka et al., 1998, Cancer Res.58(21): 4811-6.) Elevated expression of Aurora A has been detected inover 50% of colorectal, ovarian and gastric tumors and in 94% ofinvasive duct adenocarcinomas of the breast (Colorectal tumors: Bischoffet al., 1998, EMBO J. 17:3052-3065, Takahashi et al., 2000, Jpn. J.Cancer Res. 91:1007-1014, Ovarian tumors: Gritsko et al., 2003, Clin.Cancer Res. 9:1420-1426; gastric tumors: Sakakura, et al., 2001, Br. J.Cancer 84: 824-831; breast tumors: Tanaka et al., 1999, Cancer Res.59:2041-2044). High levels of Aurora A have also been reported in renal,cervical, neuroblastoma, melanoma, lymphoma, pancreatic and prostatetumor cell lines (Bischoff et al., 1998, EMBO J. 17:3052-3065; Zhou etal., 1998, Nature Genetics 20:189-193; Li et al., 2003, Clin. CancerRes. 9(3): 991-997). Amplification and over-expression of Aurora A isfurther observed in human bladder cancers and where it is associatedwith aneuploidy and aggressive clinical behavior (Sen et al., 2002, J.Natl. Cancer Inst. 94(17): 1320-1329). Isola et al. (Isola et al., 1995,Am. J. Pathology 147: 905-911) further found that amplification of theAurora A locus correlates with poor prognosis for patients withnode-negative breast cancer.

Based on the known function of the Aurora kinases, inhibition of theiractivity should disrupt mitosis leading to cell cycle arrest. In vivo,an Aurora inhibitor therefore slows tumor growth and induces regression.Stk6 inhibitors may be useful in treating gastric, bladder, breast,lung, CNS, ovarian, kidney, colon, prostate, pancreas, and cervicalcancers, melanoma, leukemia, and neuroblastoma.

Syk: Target kinase Syk (i.e., spleen tyrosine kinase) is a 72.1 kDatyrosine kinase encoded by chromosome 9q22.2 (symbol: SYK). Sykinhibitors may be useful in treating lymphomas, such as mantle celllymphoma.

TEC: Target kinase TEC (i.e., tec protein tyrosine kinase) is a 73.6 kDanon receptor tyrosine kinase encoded by chromosome 4p12 (symbol: TEC).TEC inhibitors may be useful in treating sepsis, septic shock,inflammation, rheumatoid arthritis, Crohn's disease, irritable boweldisease (IBD), and ulcerative colitis.

Tie2: Target kinase Tie2 (i.e., tyrosine kinase, endothelial) is a 125.8kDa receptor tyrosine kinase encoded by chromosome 9p21 (symbol: TEK).Tie2 inhibitors may be useful in treating cancer, arthritis (e.g.rheumatoid arthritis), and atherosclerosis.

TrkA: Target kinase TrkA (i.e., neurotrophic tyrosine kinase, receptor,type 1) is a 87.5 kDa tyrosine kinase encoded by chromosome 1q21-q22(symbol: NTRK1). TrkA inhibitors may be useful in treating pain (e.g.chronic pain, neuropathic pain), cancer, arthritis, diabeticretinopathy, macular degeneration and psoriasis.

Yes: Target kinase Yes (i.e., Yamaguchi Sarcoma Oncogene homolog 1) is a60.8 kDa tyrosine kinase encoded by chromosome 18p11.31-p11.21 (symbol:YES1). The structure of Yes comprises SH3 and SH2 domains followed by aTK domain. The YES oncogene is homologous to the Yamaguchi sarcoma virusgene, and the amino acid sequence of Yes shows a high degree of homologywith that of the SRC gene product of Rous sarcoma virus. The Yes kinaseis highly expressed in multiple mammalian cell types, including neurons,spermatozoa, platelets, and epithelial cells. The target kinase Yes isamplified and overexpressed in various cancers including esophagealsquamous cell carcinoma. Yes inhibitors may be useful in treatingcancers including esophageal squamous cell carcinoma.

Zap70: Target kinase Zap70 (i.e., Zeta-chain associated protein kinase,70 kDa) is a 69.9 kDa tyrosine kinase encoded by chromosome 2q11-13(symbol: ZAP70). Zap70 was first reported by Chan et al. (Cell 1992, 71:649-662). The mature protein comprises two SH2 domains and a TK domain.

Zap70 is crucial to the transduction of the T-cell receptor (TCR)signalling pathway, which leads ultimately to cellular differentiationand proliferation. (Weiss & Imboden 1987, Adv. Immunol. 41: 1-38). Onstimulation of the T-cell antigen receptor tyrosine phosphorylationtakes place in a number of intracellular substrates, mediated bysequential activation of two distinct families of cytoplasmic PTKs. Onesubstrate is the TCR-zeta chain, which can mediate the transduction ofextracellular stimuli into cellular effector functions. The Src kinasesLck and Fyn phosphorylate tyrosine residues on the TCR zeta-chain,contained within conserved sequences known as immunoreceptortyrosine-based activation motifs (ITAMs). The Zap70 protein associateswith the phosphorylated ITAMs in the zeta chain of the activated TCRcomplex (Chan et al., 1991, PNAS 88: 9166-9170. Recruitment of Zap70 tothe TCR and its subsequent phosphorylation and activation triggers alldownstream signaling events (Irving & Weiss, 1991, Cell 64: 891-902).This interaction is believed to be critical for TCR signaling, sincezeta-phosphopeptides that block the interaction of Zap70 with thezeta-chain also inhibit TCR signaling events (Wange et al., 1995, J.Biol. Chem. 270:944-948).

The essential role of Zap70 in T-cell function has been demonstrated inhuman patients, human T-cell lines and mice. Elder et al. (Elder et al.,1997, J. of Pedriatic Hematology/Oncology 19(6): 546-550) reportedstudies of human patient suffering from a rare form of severe combinedimmune deficiency syndrome (SCID). The patient was found to behomozygous for a 13-bp deletion involving nucleotides 1719-1731 of theZAP70 gene, resulting in premature termination 35 codons downstream andyielding a mutant protein 82 residues shorter than wildtype Zap70. Thiskind of patients have profound immunodeficiency, lack CD8+ T-cells andhave CD4+ T-Cells that are unresponsive to T-cell receptor(TCR)-mediated stimulation. Following TCR activation the CD4+ cells showsevere defects in Ca2+ mobilization, tyrosine phosphorylation ofdown-stream substrates, proliferation and IL-2 production (Elder et al.,Pedriatric Research 39: 743-748).

ZAP70 deficient human Jurkat cells also demonstrate the importantfunction of ZAP70 in T-cell receptor signaling. A Jurkat clone (p116)lacking the Zap70 protein was shown to have defects in TCR signalingwhich was correctable by re-introduction of wild type ZAP70 (Williams etal., 1998, Molecular and Cellular Biology 18 (3): 1388-1399.)

Studies of ZAP70 deficient mice also underline the crucial role of thePTK in T-cell signal transduction. ZAP70 deficient mice had neither CD4nor CD8 single-positive T cells, but human Zap70 reconstitutes both CD4and CD8 single-positive populations. Besides the defects in T-celldevelopment the TCR signalling in thymocytes was found to be profoundlyimpaired, suggesting that Zap70 is a central signalling molecule duringthymic selection for CD4 and CD8 lineage. (Negishi et al., 1995, Nature376: 435-438, Sakaguchi et al. (Sakaguchi et al. 2003, Nature 426:454-460) reported that the mouse strain SKG, which is derived from aclosed breeding colony of BALB/c mice, spontaneously develops chronicarthritis. This autosomal recessive trait was found to be caused by amutation (W163C) in the second SH2 domain of Zap70. The phenotype showedaltered signal transduction from TCRs and a change in the threshold ofT-cells to thymic selection, leading to the positive selection ofotherwise negatively selected autoimmune T-cells.

The importance of the Zap70 kinase domain function has been demonstratedby Elder et al. (Elder et al., 2001, J. Immunology 166(1): 656-661). Instudies of humans patients and mice showed that missense mutationswithin the highly conserved DL. A N motif within the kinase domain ofZap70 result in SCID. This mutation caused the loss of catalyticfunction of Zap70, resulting in defective T-cell receptor signaling. Therequirement of the catalytic function of Zap70 was further illustratedby Williams et al., who found an inactive Zap70 mutant (Lys369Arg) wasunable to restore TCR signaling in a ZAP70 deficient Jurkat cell clone(p116) (Williams et al., 1998, Mol. Cell. Biology 18 (3): 1388-1399).

Zap70 further participates in early B-cell differentiation and is aprognostic factor in chronic lymphocytic leukaemia (CLL). The course ofCLL is variable. Crespo and coworkers (Crespo et al., 2003, New Eng. J.Med. 348: 1764-1775) found that Zap70 expression by cells in CLL is asimple and reliable surrogate for the identification of immunoglobulinheavy chain variable region mutations. In the aggressive progression ofthe disease, Zap70 is associated with CLL cells expressing an unmutatedconfiguration of the immunoglobulin heavy chain variable region gene(IgVH) (Carreras et al., 2005, Journal of Pathology 205 (4): 507-513).Whereas in indolent disease, the CLL cells usually express a mutatedimmunoglobulin heavy chain variable region gene but lack expression ofZAP70. Rassenti et al. (Rassenti et al., 2004, New Eng. J. Med. 351:893-901) found that although the presence of an unmutated immunoglobulinheavy chain variable region gene in CLL patients was strongly associatedwith expression of Zap70, Zap70 was a stronger predictor of the need fortreatment in B-cell CLL. T-cell Zap70 overexpression in CLL patients wasfound to not only correlate with Zap70 levels in CLL cells, but alsowith clinical stage and disease progression. (Herishanu et al., 2005,Leukemia advance online publication).

The protein tyrosine kinase Zap70 functions in the signaling pathwaythat plays an essential role in T-cell activation and development. AfterTCR stimulation, Zap70 is associated with the receptor complex throughthe interaction of its two SH2 domains with the doubly phosphorylatedITAMs. The association of Zap70 with the TCR ITAMs facilitates itsautophosphorylation and the tyrosine phosphorylation of Zap70 mediatedby Src family PTKs, e.g. Lck and Fyn. (Iwashima et al., 1994, Science263:1136-1139). The recruitment of adaptor molecules like Lat and Slp76to Zap70 in turn couple to more distal signaling pathways including Rasand PLC-gamma (Chu et al., 2003, Journal of Biology 2 (3): 2-21).

Mutations in the ZAP70 gene are associated with the selective T-celldefect (STD) and severe combined immunodeficiency (SCID) in humanpatients. The variety of point mutations, missense mutations, deletionsand chromosomal rearrangements are identified in Zap70 all result in thesame phenotype (OMIM database with genetic mutations).

Zap70 inhibitors may be useful in treating autoimmune, inflammatory,proliferative and hyperproliferative diseases, immunologically mediateddiseases, AIDS, systemic lupus erythematosus, myasthenia gravis,atherosclerosis, rejection of transplanted organs or tissues, allograftrejection including acute and chronic allograft rejection, graft versushost disease, rheumatoid arthritis, psoriasis, systemic sclerosis,atopic dermatitis, eczematous dermatitis, alopecia, and inflammation ofthe nasal mucus membrane, including all forms of rhinitis.

III. Binding Assays

The methods of the present invention can involve assays that are able todetect the binding of compounds to a target molecule. Such binding is ata statistically significant level, preferably with a confidence level ofat least 90%, more preferably at least 95, 97, 98, 99% or greaterconfidence level that the assay signal represents binding to the targetmolecule, i.e., is distinguished from background. Preferably controlsare used to distinguish target binding from non-specific binding. Alarge variety of binding assays are known for different target types andcan be used for this invention.

Binding compounds can also be characterized by their effect on theactivity of the target molecule. Compounds of the present invention(i.e., compounds of Formula I, including Formulae Ia-Iz, and allsub-embodiments disclosed herein, or Formula II, including FormulaeIIa-IIo, and all sub-embodiments disclosed herein) may be assayed withrespect to a particular kinase to assess inhibitory concentration (IC₅₀)or excitation concentration (EC₅₀) of the compound with respect to thatkinase. The IC₅₀ (or EC₅₀) is defined as the concentration of compoundat which 50% of the activity of the target kinase activity beingmeasured is lost (or gained) relative to activity when no compound ispresent. Activity can be measured using methods known to those ofordinary skill in the art, e.g., by measuring any detectable product orsignal produced by occurrence of an enzymatic reaction, or otheractivity by a protein being measured. Compounds will have an IC₅₀ orEC₅₀ of less than 10 μM, also less than 1 μM, also less than 100 nM,also less than 10 nM or less than 1 nM.

By “background signal” in reference to a binding assay is meant thesignal that is recorded under standard conditions for the particularassay in the absence of a test compound, molecular scaffold, or ligandthat binds to the target molecule. Persons of ordinary skill in the artwill realize that accepted methods exist and are widely available fordetermining background signal.

By “standard deviation” is meant the square root of the variance. Thevariance is a measure of how spread out a distribution is. It iscomputed as the average squared deviation of each number from its mean.For example, for the numbers 1, 2, and 3, the mean is 2 and the varianceis:

$\sigma^{2} = {\frac{\left( {1 - 2} \right)^{2} + \left( {2 - 2} \right)^{2} + \left( {3 - 2} \right)^{2}}{3} = {0.667.}}$

Surface Plasmon Resonance

Binding parameters can be measured using surface plasmon resonance, forexample, with a BIAcore® chip (Biacore, Japan) coated with immobilizedbinding components. Surface plasmon resonance is used to characterizethe microscopic association and dissociation constants of reactionbetween an sFv or other ligand directed against target molecules. Suchmethods are generally described in the following references which areincorporated herein by reference. Vely F. et al., (2000) BIAcore®analysis to test phosphopeptide-SH2 domain interactions, Methods inMolecular Biology. 121:313-21; Liparoto et al., (1999) Biosensoranalysis of the interleukin-2 receptor complex, Journal of MolecularRecognition. 12:316-21; Lipschultz et al., (2000) Experimental designfor analysis of complex kinetics using surface plasmon resonance,Methods. 20(3):310-8; Malmqvist., (1999) BIACORE: an affinity biosensorsystem for characterization of biomolecular interactions, BiochemicalSociety Transactions 27:335-40; Alfthan, (1998) Surface plasmonresonance biosensors as a tool in antibody engineering, Biosensors &Bioelectronics. 13:653-63; Fivash et al., (1998) BIAcore formacromolecular interaction, Current Opinion in Biotechnology. 9:97-101;Price et al.; (1998) Summary report on the ISOBM TD-4 Workshop: analysisof 56 monoclonal antibodies against the MUC1 mucin. Tumour Biology 19Suppl 1:1-20; Malmqvist et al, (1997) Biomolecular interaction analysis:affinity biosensor technologies for functional analysis of proteins,Current Opinion in Chemical Biology. 1:378-83; O'Shannessy et al.,(1996) Interpretation of deviations from pseudo-first-order kineticbehavior in the characterization of ligand binding by biosensortechnology, Analytical Biochemistry. 236:275-83; Malmborg et al., (1995)BIAcore as a tool in antibody engineering, Journal of ImmunologicalMethods. 183:7-13; Van Regenmortel, (1994) Use of biosensors tocharacterize recombinant proteins, Developments in BiologicalStandardization. 83:143-51; and O'Shannessy, (1994) Determination ofkinetic rate and equilibrium binding constants for macromolecularinteractions: a critique of the surface plasmon resonance literature,Current Opinions in Biotechnology. 5:65-71.

BIAcore® uses the optical properties of surface plasmon resonance (SPR)to detect alterations in protein concentration bound to a dextran matrixlying on the surface of a gold/glass sensor chip interface, a dextranbiosensor matrix. In brief, proteins are covalently bound to the dextranmatrix at a known concentration and a ligand for the protein is injectedthrough the dextran matrix. Near infrared light, directed onto theopposite side of the sensor chip surface is reflected and also inducesan evanescent wave in the gold film, which in turn, causes an intensitydip in the reflected light at a particular angle known as the resonanceangle. If the refractive index of the sensor chip surface is altered(e.g., by ligand binding to the bound protein) a shift occurs in theresonance angle. This angle shift can be measured and is expressed asresonance units (RUs) such that 1000 RUs is equivalent to a change insurface protein concentration of 1 ng/mm². These changes are displayedwith respect to time along the y-axis of a sensorgram, which depicts theassociation and dissociation of any biological reaction.

High Throughput Screening (HTS) Assays

HTS typically uses automated assays to search through large numbers ofcompounds for a desired activity. Typically HTS assays are used to findnew drugs by screening for chemicals that act on a particular enzyme ormolecule. For example, if a chemical inactivates an enzyme it mightprove to be effective in preventing a process in a cell which causes adisease. High throughput methods enable researchers to assay thousandsof different chemicals against each target molecule very quickly usingrobotic handling systems and automated analysis of results.

As used herein, “high throughput screening” or “HTS” refers to the rapidin vitro screening of large numbers of compounds (libraries); generallytens to hundreds of thousands of compounds, using robotic screeningassays. Ultra high-throughput Screening (uHTS) generally refers to thehigh-throughput screening accelerated to greater than 100,000 tests perday.

To achieve high-throughput screening, it is advantageous to housesamples on a multicontainer carrier or platform. A multicontainercarrier facilitates measuring reactions of a plurality of candidatecompounds simultaneously. Multi-well microplates may be used as thecarrier. Such multi-well microplates, and methods for their use innumerous assays, are both known in the art and commercially available.

Screening assays may include controls for purposes of calibration andconfirmation of proper manipulation of the components of the assay.Blank wells that contain all of the reactants but no member of thechemical library are usually included. As another example, a knowninhibitor (or activator) of an enzyme for which modulators are sought,can be incubated with one sample of the assay, and the resultingdecrease (or increase) in the enzyme activity used as a comparator orcontrol. It will be appreciated that modulators can also be combinedwith the enzyme activators or inhibitors to find modulators whichinhibit the enzyme activation or repression that is otherwise caused bythe presence of the known the enzyme modulator. Similarly, when ligandsto a sphingolipid target are sought, known ligands of the target can bepresent in control/calibration assay wells.

Measuring Enzymatic and Binding Reactions During Screening Assays

Techniques for measuring the progression of enzymatic and bindingreactions, e.g., in multicontainer carriers, are known in the art andinclude, but are not limited to, the following.

Spectrophotometric and spectrofluorometric assays are well known in theart. Examples of such assays include the use of colorimetric assays forthe detection of peroxides, as described in Gordon, A. J. and Ford, R.A., (1972) The Chemist's Companion: A Handbook Of Practical Data.Techniques, And References, John Wiley and Sons, N.Y., Page 437.

Fluorescence spectrometry may be used to monitor the generation ofreaction products. Fluorescence methodology is generally more sensitivethan the absorption methodology. The use of fluorescent probes is wellknown to those skilled in the art. For reviews, see Bashford et al.,(1987) Spectrophotometry and Spectrofluorometry: A Practical Approach,pp. 91-114, IRL Press Ltd.; and Bell, (1981) Spectroscopy Biochemistry,Vol. I, pp. 155-194, CRC Press.

In spectrofluorometric methods, enzymes are exposed to substrates thatchange their intrinsic fluorescence when processed by the target enzyme.Typically, the substrate is nonfluorescent and is converted to afluorophore through one or more reactions. As a non-limiting example,SMase activity can be detected using the Amplex® Red reagent (MolecularProbes, Eugene, Oreg.). In order to measure sphingomyelinase activityusing Amplex® Red, the following reactions occur. First, SMasehydrolyzes sphingomyelin to yield ceramide and phosphorylcholine.Second, alkaline phosphatase hydrolyzes phosphorylcholine to yieldcholine. Third, choline is oxidized by choline oxidase to betaine.Finally, H₂O₂, in the presence of horseradish peroxidase, reacts withAmplex® Red to produce the fluorescent product, Resorufin, and thesignal therefrom is detected using spectrofluorometry.

Fluorescence polarization (FP) is based on a decrease in the speed ofmolecular rotation of a fluorophore that occurs upon binding to a largermolecule, such as a receptor protein, allowing for polarized fluorescentemission by the bound ligand. FP is empirically determined by measuringthe vertical and horizontal components of fluorophore emission followingexcitation with plane polarized light. Polarized emission is increasedwhen the molecular rotation of a fluorophore is reduced. A fluorophoreproduces a larger polarized signal when it is bound to a larger molecule(i.e. a receptor), slowing molecular rotation of the fluorophore. Themagnitude of the polarized signal relates quantitatively to the extentof fluorescent ligand binding. Accordingly, polarization of the “bound”signal depends on maintenance of high affinity binding.

FP is a homogeneous technology and reactions are very rapid, takingseconds to minutes to reach equilibrium. The reagents are stable, andlarge batches may be prepared, resulting in high reproducibility.Because of these properties, FP has proven to be highly automatable,often performed with a single incubation with a single, premixed,tracer-receptor reagent. For a review, see Owicki et al., (1997).Application of Fluorescence Polarization Assays in High-ThroughputScreening, Genetic Engineering News, 17:27.

FP is particularly desirable since its readout is independent of theemission intensity (Checovich, W. J., et al., (1995) Nature 375:254-256;Dandliker, W. B., et al. (1981) Methods in Enzymology 74:3-28) and isthus insensitive to the presence of colored compounds that quenchfluorescence emission. FP and FRET (see below) are well-suited foridentifying compounds that block interactions between sphingolipidreceptors and their ligands. See, for example, Parker et al., (2000)Development of high throughput screening assays using fluorescencepolarization: nuclear receptor-ligand-binding and kinase/phosphataseassays, J Biomol Screen 5:77-88.

Fluorophores derived from sphingolipids that may be used in FP assaysare commercially available. For example, Molecular Probes (Eugene,Oreg.) currently sells sphingomyelin and one ceramide fluorophores.These are, respectively,N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosylphosphocholine (BODIPY® FL C5-sphingomyelin);N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl)sphingosylphosphocholine (BODIPY® FL C12-sphingomyelin); andN-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine(BODIPY®FL C5-ceramide). U.S. Pat. No. 4,150,949, (Immunoassay forgentamicin), discloses fluorescein-labelled gentamicins, includingfluoresceinthiocarbanyl gentamicin. Additional fluorophores may beprepared using methods well known to the skilled artisan.

Exemplary normal-and-polarized fluorescence readers include thePOLARION® fluorescence polarization system (Tecan AG, Hombrechtikon,Switzerland). General multiwell plate readers for other assays areavailable, such as the VERSAMAX® reader and the SPECTRAMAX® multiwellplate spectrophotometer (both from Molecular Devices).

Fluorescence resonance energy transfer (FRET) is another useful assayfor detecting interaction and has been described. See, e.g., Heim etal., (1996) Curr. Biol. 6:178-182; Mitra et al., (1996) Gene 173:13-17;and Selvin et al., (1995) Meth. Enzymol. 246:300-345. FRET detects thetransfer of energy between two fluorescent substances in closeproximity, having known excitation and emission wavelengths. As anexample, a protein can be expressed as a fusion protein with greenfluorescent protein (GFP). When two fluorescent proteins are inproximity, such as when a protein specifically interacts with a targetmolecule, the resonance energy can be transferred from one excitedmolecule to the other. As a result, the emission spectrum of the sampleshifts, which can be measured by a fluorometer, such as a fMAX multiwellfluorometer (Molecular Devices, Sunnyvale Calif.).

Scintillation proximity assay (SPA) is a particularly useful assay fordetecting an interaction with the target molecule. SPA is widely used inthe pharmaceutical industry and has been described (Hanselman et al.,(1997) J. Lipid Res. 38:2365-2373; Kahl et al., (1996) Anal. Biochem.243:282-283; Undenfriend et al., (1987) Anal Biochem. 161:494-500). Seealso U.S. Pat. Nos. 4,626,513 and 4,568,649, and European Patent No.0,154,734. One commercially available system uses FLASHPLATE®scintillant-coated plates (NEN Life Science Products, Boston, Mass.).

The target molecule can be bound to the scintillator plates by a varietyof well known means. Scintillant plates are available that arederivatized to bind to fusion proteins such as GST, His6 or Flag fusionproteins. Where the target molecule is a protein complex or a multimer,one protein or subunit can be attached to the plate first, then theother components of the complex added later under binding conditions,resulting in a bound complex.

In a typical SPA assay, the gene products in the expression pool willhave been radiolabeled and added to the wells, and allowed to interactwith the solid phase, which is the immobilized target molecule andscintillant coating in the wells. The assay can be measured immediatelyor allowed to reach equilibrium. Either way, when a radiolabel becomessufficiently close to the scintillant coating, it produces a signaldetectable by a device such as a TOPCOUNT NXT® microplate scintillationcounter (Packard Bioscience Co., Meriden Conn.). If a radiolabeledexpression product binds to the target molecule, the radiolabel remainsin proximity to the scintillant long enough to produce a detectablesignal.

In contrast, the labeled proteins that do not bind to the targetmolecule, or bind only briefly, will not remain near the scintillantlong enough to produce a signal above background. Any time spent nearthe scintillant caused by random Brownian motion will also not result ina significant amount of signal. Likewise, residual unincorporatedradiolabel used during the expression step may be present, but will notgenerate significant signal because it will be in solution rather thaninteracting with the target molecule. These non-binding interactionswill therefore cause a certain level of background signal that can bemathematically removed. If too many signals are obtained, salt or othermodifiers can be added directly to the assay plates until the desiredspecificity is obtained (Nichols et al., (1998) Anal. Biochem.257:112-119).

IV. Kinase Activity Assays

A number of different assays for kinase activity can be utilized forassaying for active modulators and/or determining specificity of amodulator for a particular kinase or group or kinases. In addition tothe assay mentioned in the Examples below, one of ordinary skill in theart will know of other assays that can be utilized and can modify anassay for a particular application. For example, numerous papersconcerning kinases describe assays that can be used.

Additional alternative assays can employ binding determinations. Forexample, this sort of assay can be formatted either in a fluorescenceresonance energy transfer (FRET) format, or using an AlphaScreecn(amplified luminescent proximity homogeneous assay) format by varyingthe donor and acceptor reagents that are attached to streptavidin or thephosphor-specific antibody.

V. Organic Synthetic Techniques

The versatility of computer-based modulator design and identificationlies in the diversity of structures screened by the computer programs.The computer programs can search databases that contain very largenumbers of molecules and can modify modulators already complexed withthe enzyme with a wide variety of chemical functional groups. Aconsequence of this chemical diversity is that a potential modulator ofkinase function may take a chemical form that is not predictable. A widearray of organic synthetic techniques exist in the art to meet thechallenge of constructing these potential modulators. Many of theseorganic synthetic methods are described in detail in standard referencesources utilized by those skilled in the art. One example of such areference is March, 1994, Advanced Organic Chemistry; Reactions,Mechanisms and Structure, New York, McGraw Hill. Thus, the techniquesuseful to synthesize a potential modulator of kinase function identifiedby computer-based methods are readily available to those skilled in theart of organic chemical synthesis.

Regarding the synthetic examples described herein, solvents includepolar and non-polar solvents known to those of skill in the art,including polar aprotic and polar protic solvents. Polar solventsinclude, without limitation, protic solvents such as methanol, ethanol,isopropyl alcohol, t-butanol, n-butanol, acetic acid, formic acid orwater, or aprotic solvents such as tetrahydrofuran (THF), acetonitrile,dioxane, methylene chloride, dimethylsulfoxide (DMSO), acetone,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), ethyl acetate,1,2-dimethoxyethane, 1,2-dichloroethane, chloroform, 1,2-dichloroethane,or pyridine. Polar solvents include a mixture of water with any of theabove, or a mixture of any two or more of the above. Apolar solventsinclude, without limitation, toluene, benzene, chlorobenzene, xylenesand hexanes.

Regarding the synthetic examples described herein, reducing agentincludes, without limitation, a reducing agent such as catalyticreducing agents using hydrogen and transition metal catalysts such aspalladium, platinum, rhodium, etc. (e.g. Pt/acetic acid/H₂); a mixtureof trifluoroacetic acid and triethylsilane, borane tetrahydrofurancomplex, diborane, borane dimethylsulfide complex, and a combination ofsodium borohydride and boron trifluoride; metals such as reduced iron,zinc powder, magnesium etc.; metal hydrogen complex compounds such asalkali metal borohydrides (for example, potassium borohydride, sodiumborohydride, lithium borohydride, zinc borohydride, sodiumtriacetoxyborohydride, etc.), aluminum lithium hydride, etc.; metalhydrides such as sodium hydride, etc.; organic tin compounds(triphenyltin hydride, etc.); and metal salts such as nickel compounds,zinc compounds, tin compounds (for example tin(II) chloride), andsamarium iodide/pivalic acid/hexamethylphosphoric triamide.

Regarding the synthetic examples described herein, oxidizing agentincludes, without limitation, an oxidizing agent such as Dess-Martinreagent, TEMPO (2,2,6,6-tetramethylpiperidine-N-oxide), DDQ(2,3-Dichloro-5,6-dicyano-1,4-benzoquinone), PDC (pyridiniumdichromate), PCC (pyridinium chlorochromate), Pyridine.SO3, Chromiumtrioxide, p-nitroperbenzoic acid, magnesium monoperoxyphthalate, sodiumperiodate, potassium periodate, hydrogen peroxide, urea peroxide, alkalimetal bromates, cumene hydroperoxide, tert-butyl peroxide, peracids suchas performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoicacid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid and the like;sodium metaperiodate, bichromic acid; bichromates such as sodiumbichromate, potassium bichromate; permanganic acid; permanganates suchas potassium permanganate, sodium permanganate; and lead salts such aslead tetraacetate.

VI. Alternative Compound Forms or Derivatives

Compounds contemplated herein are described with reference to bothgeneric formulae and specific compounds. In addition, inventioncompounds may exist in a number of different forms or derivatives, allwithin the scope of the present invention. These include, for example,tautomers, stereoisomers, racemic mixtures, regioisomers, salts,prodrugs (e.g., carboxylic acid esters), solvated forms, differentcrystal forms or polymorphs, and active metabolites.

(a) Tautomers, Stereoisomers, Regioisomers, and Solvated Forms

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood that theformulae provided herein are intended to represent any tautomeric formof the depicted compounds and are not to be limited merely to thespecific tautomeric form depicted by the drawings of the formulae.

Likewise, some of the compounds according to the present invention mayexist as stereoisomers, i.e. having the same atomic connectivity ofcovalently bonded atoms yet differing in the spatial orientation of theatoms. For example, compounds may be optical stereoisomers, whichcontain one or more chiral centers, and therefore, may exist in two ormore stereoisomeric forms (e.g. enantiomers or diastereomers). Thus,such compounds may be present as single stereoisomers (i.e., essentiallyfree of other stereoisomers), racemates, and/or mixtures of enantiomersand/or diastereomers. As another example, stereoisomers includegeometric isomers, such as cis- or trans-orientation of substituents onadjacent carbons of a double bond. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe present invention. Unless specified to the contrary, all suchstereoisomeric forms are included within the formulae provided herein.

In some embodiments, a chiral compound of the present invention is in aform that contains at least 80% of a single isomer (60% enantiomericexcess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70%e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5%(95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understoodby those skilled in the art, an optically pure compound having onechiral center is one that consists essentially of one of the twopossible enantiomers (i.e., is enantiomerically pure), and an opticallypure compound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. In some embodiments,the compound is present in optically pure form.

For compounds in which synthesis involves addition of a single group ata double bond, particularly a carbon-carbon double bond, the additionmay occur at either of the double bond-linked atoms. For such compounds,the present invention includes both such regioisomers.

Additionally, the formulae are intended to cover solvated as well asunsolvated forms of the identified structures. For example, theindicated structures include both hydrated and non-hydrated forms. Otherexamples of solvates include the structures in combination with asuitable solvent such as isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine.

(b) Prodrugs and Metabolites

In addition to the present formulae and compounds described herein, theinvention also includes prodrugs (generally pharmaceutically acceptableprodrugs), active metabolic derivatives (active metabolites), and theirpharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. For example, some prodrugs are esters of the activecompound; during metabolysis, the ester group is cleaved to yield theactive drug. Also, some prodrugs are activated enzymatically to yieldthe active compound, or a compound which, upon further chemicalreaction, yields the active compound.

In this context, a common example or a prodrug is an alkyl ester of acarboxylic acid. Relative to compounds of Formula I, further examplesinclude, without limitation, an amide or carbamate derivative at the1-position nitrogen of the azaindole core.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollow types:

Oxidative reactions: Oxidative reactions are exemplified withoutlimitation to reactions such as oxidation of alcohol, carbonyl, and acidfunctionalities, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive reactions: Reductive reactions are exemplified withoutlimitation to reactions such as reduction of carbonyl functionalities,reduction of alcohol functionalities and carbon-carbon double bonds,reduction of nitrogen-containing function groups, and other reductionreactions.

Reactions without change in the oxidation state: Reactions withoutchange in the state of oxidation are exemplified without limitation toreactions such as hydrolysis of esters and ethers, hydrolytic cleavageof carbon-nitrogen single bonds, hydrolytic cleavage of non-aromaticheterocycles, hydration and dehydration at multiple bonds, new atomiclinkages resulting from dehydration reactions, hydrolyticdehalogenation, removal of hydrogen halide molecule, and other suchreactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,incorporated herein by reference). Such carrier prodrugs are oftenadvantageous for orally administered drugs. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof hydroxyl groups with lipophilic carboxylic acids, or of carboxylicacid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.

Prodrugs may proceed from prodrug form to active form in a single stepor may have one or more intermediate forms which may themselves haveactivity or may be inactive.

Metabolites, e.g., active metabolites overlap with prodrugs as describedabove, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic process in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using routinetechniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, DrugDev Res 34:220-230; Wermuth, supra.

(c) Pharmaceutically Acceptable Salts

Compounds can be formulated as or be in the form of pharmaceuticallyacceptable salts. Contemplated pharmaceutically acceptable salt formsinclude, without limitation, mono, bis, tris, tetrakis, and so on.Pharmaceutically acceptable salts are non-toxic in the amounts andconcentrations at which they are administered. The preparation of suchsalts can facilitate the pharmacological use by altering the physicalcharacteristics of a compound without preventing it from exerting itsphysiological effect. Useful alterations in physical properties includelowering the melting point to facilitate transmucosal administration andincreasing the solubility to facilitate administering higherconcentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, chloride, hydrochloride, fumarate, maleate,phosphate, sulfamate, acetate, citrate, lactate, tartrate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts canbe obtained from acids such as hydrochloric acid, maleic acid, sulfuricacid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lacticacid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamicacid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts suchas those containing benzathine, chloroprocaine, choline, diethanolamine,ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine,aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium,alkylamine, and zinc, when acidic functional groups, such as carboxylicacid or phenol are present. For example, see Remington's PharmaceuticalSciences, 19th ed., Mack Publishing Co., Easton, Pa., Vol. 2, p. 1457,1995. Such salts can be prepared using the appropriate correspondingbases.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent.

Thus, for example, if the particular compound is a base, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha-hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

Similarly, if the particular compound is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include organic salts derived from aminoacids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary,secondary, and tertiary amines, and cyclic amines, such ashydroxyethylpyrrolidine, piperidine, morpholine or piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium. Further examples ofpharmaceutically acceptable salts of compounds of Formulae I-IIIinclude, without limitation, the mono-sodium and bis-potassium saltsthereof.

The pharmaceutically acceptable salt of the different compounds may bepresent as a complex. Examples of complexes include 8-chlorotheophyllinecomplex (analogous to, e.g., dimenhydrinate: diphenhydramine8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrininclusion complexes.

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound.

(d) Polymorphic Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, all of which are intended to be within the scopeof the present invention and specified formulae.

VII. Administration

The methods and compounds will typically be used in therapy for humansubjects. However, they may also be used to treat similar or identicalindications in other animal subjects. In this context, the terms“subject,” “animal subject,” and the like refer to human and non-humanvertebrates, e.g. mammals, such as non-human primates, sports andcommercial animals, e.g., equines, bovines, porcines, ovines, rodents,and pets, e.g., canines and felines.

Suitable dosage forms, in part, depend upon the use or the route ofadministration, for example, oral, transdermal, transmucosal, inhalantor by injection (parenteral). Such dosage forms should allow thecompound to reach target cells. Other factors are well known in the art,and include considerations such as toxicity and dosage forms that retardthe compound or composition from exerting its effects. Techniques andformulations generally may be found in The Science and Practice ofPharmacy, 21^(st) edition, Lippincott, Williams and Wilkins,Philadelphia, Pa., 2005 (hereby incorporated by reference herein).

Compounds of the present invention, i.e. Formula I, can be formulated aspharmaceutically acceptable salts.

Carriers or excipients can be used to produce compositions. The carriersor excipients can be chosen to facilitate administration of thecompound. Examples of carriers include calcium carbonate, calciumphosphate, various sugars such as lactose, glucose, or sucrose, or typesof starch, cellulose derivatives, gelatin, vegetable oils, polyethyleneglycols and physiologically compatible solvents. Examples ofphysiologically compatible solvents include sterile solutions of waterfor injection (WFI), saline solution, and dextrose.

The compounds can be administered by different routes includingintravenous, intraperitoneal, subcutaneous, intramuscular, oral,transmucosal, rectal, transdermal, or inhalant. Oral administration ispreferred. For oral administration, for example, the compounds can beformulated into conventional oral dosage forms such as capsules,tablets, and liquid preparations such as syrups, elixirs, andconcentrated drops.

For inhalants, compounds of the invention may be formulated as drypowder or a suitable solution, suspension, or aerosol. Powders andsolutions may be formulated with suitable additives known in the art.For example, powders may include a suitable powder base such as lactoseor starch, and solutions may comprise propylene glycol, sterile water,ethanol, sodium chloride and other additives, such as acid, alkali andbuffer salts. Such solutions or suspensions may be administered byinhaling via spray, pump, atomizer, or nebulizer, and the like. Thecompounds of the invention may also be used in combination with otherinhaled therapies, for example corticosteroids such as fluticasoneproprionate, beclomethasone dipropionate, triamcinolone acetonide,budesonide, and mometasone furoate; beta agonists such as albuterol,salmeterol, and formoterol; anticholinergic agents such as ipratropriumbromide or tiotropium; vasodilators such as treprostinal and iloprost;enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies;an oligonucleotide, such as single or double stranded DNA or RNA, siRNA;antibiotics such as tobramycin; muscarinic receptor antagonists;leukotriene antagonists; cytokine antagonists; protease inhibitors;cromolyn sodium; nedocril sodium; and sodium cromoglycate.

Pharmaceutical preparations for oral use can be obtained, for example,by combining the active compounds with solid excipients, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations, for example, maize starch, wheat starch, rice starch,potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegratingagents may be added, such as the cross-linked polyvinylpyrrolidone,agar, or alginic acid, or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally contain,for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel,polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dye-stuffs orpigments may be added to the tablets or dragee coatings foridentification or to characterize different combinations of activecompound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols (PEGs). In addition, stabilizers may be added.

Alternatively, injection (parenteral administration) may be used, e.g.,intramuscular, intravenous, intraperitoneal, and/or subcutaneous. Forinjection, the compounds of the invention are formulated in sterileliquid solutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. In addition, the compounds may be formulated in solid form andredissolved or suspended immediately prior to use. Lyophilized forms canalso be produced.

Administration can also be by transmucosal, topical, or transdermalmeans. For transmucosal, topical or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, bile salts andfusidic acid derivatives. In addition, detergents may be used tofacilitate permeation. Transmucosal administration, for example, may bethrough nasal sprays or suppositories (rectal or vaginal). The topicalcompositions of this invention are formulated preferably as oils,creams, lotions, ointments and the like by choice of appropriatecarriers known in the art. Suitable carriers include vegetable ormineral oils, white petrolatum (white soft paraffin), branched chainfats or oils, animal fats and high molecular weight alcohol (greaterthan C₁₂). The preferred carriers are those in which the activeingredient is soluble. Emulsifiers, stabilizers, humectants andantioxidants may also be included as well as agents imparting color orfragrance, if desired. Creams for topical application are preferablyformulated from a mixture of mineral oil, self-emulsifying beeswax andwater in which mixture the active ingredient, dissolved in a smallamount solvent (e.g., an oil), is admixed. Additionally, administrationby transdermal means may comprise a transdermal patch or dressing suchas a bandage impregnated with an active ingredient and optionally one ormore carriers or diluents known in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundIC₅₀, the biological half-life of the compound, the age, size, andweight of the subject, and the disorder associated with the subject. Theimportance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be between about 0.01and 50 mg/kg, preferably 0.1 and 20 mg/kg of the subject being treated.Multiple doses may be used.

The compounds of the invention may also be used in combination withother therapies for treating the same disease. Such combination useincludes administration of the compounds and one or more othertherapeutics at different times, or co-administration of the compoundand one or more other therapies. In some embodiments, dosage may bemodified for one or more of the compounds of the invention or othertherapeutics used in combination, e.g., reduction in the amount dosedrelative to a compound or therapy used alone, by methods well known tothose of ordinary skill in the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than acompound of the present invention, or at the same time as a compound ofthe invention. Use in combination also includes use with a therapy ormedical procedure that is administered once or infrequently, such assurgery, along with a compound of the invention administered within ashort time or longer time before or after the other therapy orprocedure. In some embodiments, the present invention provides fordelivery of compounds of the invention and one or more other drugtherapeutics delivered by a different route of administration or by thesame route of administration. The use in combination for any route ofadministration includes delivery of compounds of the invention and oneor more other drug therapeutics delivered by the same route ofadministration together in any formulation, including formulations wherethe two compounds are chemically linked in such a way that they maintaintheir therapeutic activity when administered. In one aspect, the otherdrug therapy may be co-administered with one or more compounds of theinvention. Use in combination by co-administration includesadministration of co-formulations or formulations of chemically joinedcompounds, or administration of two or more compounds in separateformulations within a short time of each other (e.g. within an hour, 2hours, 3 hours, up to 24 hours), administered by the same or differentroutes. Co-administration of separate formulations includesco-administration by delivery via one device, for example the sameinhalant device, the same syringe, etc., or administration from separatedevices within a short time of each other. Co-formulations of compoundsof the invention and one or more additional drug therapies delivered bythe same route includes preparation of the materials together such thatthey can be administered by one device, including the separate compoundscombined in one formulation, or compounds that are modified such thatthey are chemically joined, yet still maintain their biologicalactivity. Such chemically joined compounds may have a linkage that issubstantially maintained in vivo, or the linkage may break down in vivo,separating the two active components.

EXAMPLES

Examples related to the present invention are described below. In mostcases, alternative techniques can be used. The examples are intended tobe illustrative and are not limiting or restrictive to the scope of theinvention. In some examples, the mass spectrometry result indicated fora compound may have more than one value due to the isotope distributionof an atom in the molecule, such as a compound having a bromo or chlorosubstituent.

Example 1 Synthesis of propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amideP-0773 and related compounds

Compound P-0773 was synthesized in five steps from2,4-difluoro-phenylamine 42 as shown in Scheme 13.

Step 1—Preparation of 3-amino-2,6-difluoro-benzoic acid benzyl ester(43)

To 2,4-difluoro-phenylamine (42, 5.11 mL. 50.7 mmol) in tetrahydrofuran(250 mL), cooled with dry ice/acetone bath under an atmosphere ofnitrogen, was added n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4mmol) slowly. After 30 minutes, 1,2-Bis-(chloro-dimethyl-silanyl)-ethane(11.5 g, 53.4 mmol) dissolved in tetrahydrofuran (40.0 mL) was added tothe reaction slowly. After 1 hour, n-butyllithium (1.60 M in hexane,31.9 mL, 51.0 mmol) was added slowly to the reaction. The reaction wasstirred at −78° C. for 30 minutes and then allowed to warm to roomtemperature over 40 minutes. The reaction was cooled to −78° C.,followed by addition of n-butyllithium (1.60 M in hexane, 35.1 mL, 56.2mmol) slowly. After 70 minutes, benzyl chloroformate (7.97 mL, 55.8mmol) was added to the reaction. The reaction mixture was stirred at−78° C. overnight followed by addition of 2 N HCl (120 mL). The reactionwas allowed to warm to room temperature for 2 hours. The organic layerwas separated. The aqueous layer was basified with potassium carbonateand extracted with ethyl acetate. The organic layers were combined andwashed with brine, dried over anhydrous sodium sulfate, filtrated andconcentrated. The desired compound was isolated by silica gel columnchromatography (ethyl acetatehexane 20%) to give a colorless oil (43,10.6 g, 79.7%). MS (ESI) [M+H⁺]⁺=264.1.

Step 2—Preparation of 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoicacid benzyl ester (44)

To 3-amino-2,6-difluoro-benzoic acid benzyl ester (43, 6.00 g, 22.8mmol) in methylene chloride (150 mL) was added pyridine (2.76 mL, 34.2mmol) and propane-1-sulfonyl chloride (3.80 mL, 33.8 mmol). The reactionwas stirred at room temperature overnight. Then the reaction was pouredinto water, and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtrated andconcentrated. The desired compound was isolated with silica gel columnchromatography to give a colorless oil (44, 7.0 g, 83.1%). MS (ESI)[M+H⁺]⁺=370.1.

Step 3—Preparation of 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoicacid (45)

To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester(44, 2.0 g, mmol) in methanol (30 mL) was added 20% palladium hydroxideon carbon (100 mg). The reaction was stirred under hydrogen at 1 atm for15 minutes. The reaction was filtrated and concentrated to give whitesolid 45 that was used in the next step.

Step 4—Preparation of 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoylchloride (46)

To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid (45, 1.50 g,5.4 mmol) was added toluene (7.0 mL) and thionyl chloride (15.0 mL, 0.21mmol). The reaction was heated to reflux for 3 hours. The reaction wasconcentrated to give crude compound that was used in the next step.

Step 5—Preparation of propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide(P-0773)

To aluminum trichloride (8.89 g, 66.7 mmol) was added methylene chloride(150 mL) under an atmosphere of nitrogen below 5° C. Into this,5-bromo-7-azaindole (67, 1.64 g, 8.34 mmol) in methylene chloride (20mL) was added. The reaction was stirred for 60.0 minutes and2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (46, 3.50 g,11.8 mmol) in methylene chloride (20 mL) was added. The reaction wasstirred for 6 hours and warmed to room temperature overnight. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, filtrated andconcentrated. The desired compound was isolated by silica gel columnchromatography (methylene chloride/methanol 5%) to give a white solid(P-0773, 1.2 g, 31.4%). MS (ESI) [M+H⁺]⁺=460.0, 462.0.

N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-methanesulfonamideP-0868

was prepared following the protocol of Scheme 13, substitutingpropane-1-sulfonyl chloride with methanesulfonyl chloride in Step 2 and2,4-difluoro-phenylamine with 4-chloro-2-fluoro-phenylamine in Step 1.MS (ESI) [M−H⁺]⁻=443.9, 445.9.

N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-methanesulfonamideP-0162

was prepared following the protocol of Scheme 13, substitutingpropane-1-sulfonyl chloride with methanesulfonyl chloride in Step 2.This was isolated and reacted further (50 mg, 0.10 mmol) in methanol (20mL) by adding 20% palladium hydroxide on carbon (53 mg). The reactionwas stirred under hydrogen at 40 psi for 12 hours. The reaction mixturewas filtered and concentrated to give product methanesulfonic acid[2,4-difluoro-3-1H-pyrrolo-[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0811 (40 mg, 95%).

MS (ESI) [M+H⁺]⁺=352.3.

N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamideP-0798 andN-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide

were prepared following the protocol of Scheme 13, substitutingpropane-1-sulfonyl chloride with benzenesulfonyl chloride and3-fluoro-benzenesulfonyl chloride, respectively, in Step 2. P-0798 MS(ESI) [M−H⁺]⁻=489.9, 491.9.

Propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-amideP-0805

was prepared following the protocol of Scheme 13, substituting2,4-difluoro-phenylamine with 4-chloro-2-fluoro-phenylamine in Step 1.MS (ESI) [M−H⁺]⁻=471.9, 473.9.

Propane-1-sulfonic acid[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0007

was prepared following the protocol of Scheme 13, substituting5-bromo-7-azaindole with 7-azaindole in Step 5. MS (ESI) [M+H⁺]⁺=380.1.

Propane-1-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0806

was prepared following the protocol of Scheme 13, substituting5-bromo-7-azaindole with 5-methoxy-7-azaindole 104 (prepared asdescribed in Example 16) in Step 5. MS (ESI) [M−H⁺]⁻=410.1.

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl)-methanoneP-0265

was prepared using the protocol of steps 4 and 5 of Scheme 13,substituting 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid with2-fluoro-3-methoxy-benzoic acid in Step 4. MS (ESI) [M−H⁺]⁻=347, 349.

N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-methanesulfonamideP-0170

was prepared using the protocol of steps 2, 4, and 5 of Scheme 13,substituting 3-amino-2,6-difluoro-benzoic acid benzyl ester with5-amino-2-fluoro-benzoic acid and propane-1-sulfonyl chloride withmethanesulfonyl chloride in Step 2, to provide the acid that is carriedthrough in Step 4. MS (ESI) [M−H⁺]⁻=410.0, 412.0.

N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl]-methanesulfonamideP-0180

was prepared using the protocol of steps 2, 4, and 5 of Scheme 13,substituting 3-amino-2,6-difluoro-benzoic acid benzyl ester with3-amino-2-methyl-benzoic acid and propane-1-sulfonyl chloride withmethanesulfonyl chloride in Step 2, to provide the acid that is carriedthrough in Step 4. MS (ESI) [M−H⁺]⁻=405.9, 407.9.

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-chloro-2-fluoro-phenyl)-methanoneP-0299

was prepared using the protocol of Step 5 of Scheme 13, substituting2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride with3-chloro-2-fluoro-benzoyl chloride. MS (ESI) [M−H⁺]⁻=350.9, 352.9.

Example 2 Synthesis of Propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amideP-0955 and Related Compounds

Compound P-0955 was synthesized in six steps from4-chloro-2-fluoro-phenylamine 47 as shown in Scheme 14.

Step 1—Preparation of 3-Amino-6-chloro-2-fluoro-benzoic acid benzylester (48)

To 4-chloro-2-fluoro-phenylamine (47, 6.30 mL, 57.0 mmol) intetrahydrofuran (300 mL), cooled with dry ice/acetone bath under anatmosphere of nitrogen, was added n-butyllithium (2.500 M in hexane,24.4 mL) slowly. After 20 minutes,1,2-Bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0 mmol) dissolvedin tetrahydrofuran (40.0 mL) was added to the reaction slowly. After 1hour, n-butyllithium (2.50 M in hexane, 25.0 mL) was added slowly to thereaction. The reaction was stirred at −78° C. for 20 minutes and allowedto warm to room temperature over 60 minutes. The reaction was cooled to−78° C., followed by addition of n-butyllithium (2.50 M in hexane, 26.0mL) slowly. After 80 minutes, benzyl chloroformate (10.0 mL, 70.0 mmol)was added to the reaction. The reaction mixture was stirred at −78° C.overnight followed by addition of water (80 mL) and concentratedhydrochloric acid (25 mL). The reaction was allowed to warm to roomtemperature for 2 hours. The organic layer was separated and the aqueouslayer was basified with potassium carbonate and extracted with ethylacetate. The organic layers were combined and washed with brine, driedover anhydrous sodium sulfate, filtrated and concentrated. The desiredcompound was isolated by silica gel column chromatography (ethylacetate/hexane 20%) to give a colorless oil (48, 12.5 g, 78.3%). MS(ESI) [M+H⁺]⁺=280.0.

Step 2—Preparation of6-chiro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester(49)

To 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (48, 1.20 g, 4.3mmol) in methylene chloride (28 mL) was added pyridine (0.52 mL, 6.4mmol) and propane-1-sulfonyl chloride (0.685 g, 4.8 mmol). The reactionwas stirred at room temperature overnight. The reaction was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtrated andconcentrated. The desired compound was isolated with silica gel columnchromatography to give a colorless oil (49, 960 mg, 58.0%). MS (ESI)[M−H⁺]⁻=384.1.

Step 3—Preparation of6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (115)

To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzylester (49, 6.00 g, 15.6 mmol) in tetrahydrofuran (100 mL) was added 1.0M aqueous potassium hydroxide (100 mL). The reaction was heated toreflux overnight. The reaction was poured into water, acidified to pH 2with 1 N hydrochloric acid and extracted with ethyl acetate. The organicportion was dried over anhydrous sodium sulfate, filtrated andconcentrated to give a white solid 115 (3.95 g, 85.8%).

Step 4—Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid(50)

To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (115, 0.69g, 2.3 mmol) in methanol (10 mL) was added 20% palladium hydroxide oncarbon (200 mg). The reaction was stirred under hydrogen at 50 psi for 2hours. The reaction was filtrated and concentrated to give white solid50 that was used in the next step. MS (ESI) [M−H⁺]⁻=260.1.

Step 5—Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoylchloride (51)

To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (50, 1.17 g, 4.5mmol) was added thionyl chloride (10.0 mL). The reaction was heated toreflux for 3 hours. The reaction was concentrated to give crude compound51 that was used in the next step.

Step 6—Preparation of Propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide(P-0955)

Aluminum trichloride (2.52 g, 18.9 mmol) and methylene chloride (60.0mL) were combined under an atmosphere of nitrogen. Into the reactionmixture, was added 5-bromo-7-azaindole (67, 630.0 mg, 3.2 mmol) inmethylene dichloride (20.0 mL). The reaction was stirred at roomtemperature for 70 minutes, then2-fluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (51, 0.749 g, 2.68mmol) in methylene chloride (20 mL) was added. The reaction was stirredat room temperature for 2 hours. The reaction was poured into water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 30% ethyl acetate inhexane to give compound P-0955 (65 mg, 5.5%). MS (ESI) [M+H⁺]⁺=440.2,442.2.

Using the protocol of Scheme 14, substituting 5-bromo-azaindole witheither 5-chloro-7-azaindole (80, prepared as described in Example 9),5-fluoro-7-azaindole (81, prepared as described in Example 9) or7-azaindole in Step 6, propane-1-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amideP-1013 (MS (ESI) [M−H⁺]⁻=394.1), propane-1-sulfonic acid[2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-1028 (MS (ESI) [M−H⁺]⁻=378.1), and propane-1-sulfonic acid[2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1056(MS (ESI) [M+H⁺]⁺=362.2) were prepared, respectively;

Example 3 Propane-1-sulfonic acid[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0088 and Related Compounds

Compound P-0088 was synthesized in one step from propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amideP-0773 by Suzuki coupling ((Muyaura and Suzuki, Chem. Rev. 1995,95:2457) as shown in Scheme 15.

Step 1—Preparation of propane-1-sulfonic acid[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide(P-0088)

To propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide(P-0773, prepared as described in Example 1, 65.0 mg, 0.14 mmol) inacetonitrile (4.0 mL) was added pyridine-3-boronic acid (609, 25.0 mg,0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 1.0% mmol)and aqueous potassium carbonate (1.0 M, 2.0 mL). The reaction was heatedto 160° C. for 10 minutes in a CEM Discover microwave instrument. Thereaction was poured into water, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtrated and concentrated. The desired compound was isolatedby silica gel column chromatography (methylene chloride/methanol 5%) togive a white solid (P-0088, 30 mg, 46.9%). MS (ESI) [M+H⁺]⁺=457.2.

Additional compounds were prepared following the protocol of Scheme 15,optionally replacing propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amideP-0773 with an appropriate 5-bromo azaindole and/or pyridine-3-boronicacid 609 with an appropriate boronic acid or boronic acid ester. The5-bromo azaindole used was synthesized as described in either Example 1,2, 5, 10, or 73. The following compounds were made following thisprocedure:

-   N-[2-Methyl-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide    (P-0082),-   N-[2-Methyl-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide    (P-0121),-   N-[4-Fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide    (P-0079),-   N-[4-Fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide    (P-0308),-   N-{4-Fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide    (P-0156),-   N-{4-Fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide    (P-0297),-   3-[3-(2-Fluoro-5-methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide    (P-0228),-   3-[3-(2-Fluoro-5-hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide    (P-0037),-   (2-Fluoro-5-hydroxy-phenyl)-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone    (P-0008),-   N-{3-[3-(2-Fluoro-5-hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-0716),-   N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide    (P-0700),-   N-{4-Chloro-2-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide    (P-0841),-   N-[4-Chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide    (P-0734),-   N-{4-Chloro-2-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide    (P-0745),-   N-{2,4-Difluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-methanesulfonamide    (P-0746),-   3-[3-(2,6-Difluoro-3-methanesulfonylamino-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide    (P-0721),-   N-[2,4-Difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-methanesulfonamide    (P-0184),-   N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-0685),-   Propane-1-sulfonic acid    [4-chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0753),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0636),-   Propane-1-sulfonic acid    [4-chloro-2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0776)-   Propane-1-sulfonic acid    {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide    (P-0956),-   Propane-1-sulfonic acid    {3-[5-(4-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide    (P-0889),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-0877),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-0912),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-0874),-   Propane-1-sulfonic acid    {3-[5-(3-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide    (P-0876),-   Propane-1-sulfonic acid    [2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0897),-   Propane-1-sulfonic acid    {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide    (P-1009),-   (2-Fluoro-3-hydroxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0027),-   (3-Chloro-2-fluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0165), 5-phenyl-1H-pyrrolo[2,3-b]pyridine,-   Propane-1-sulfonic acid    [2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1251),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1259),-   Propone 1-sulfonic acid    {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1260),-   Propane-1-sulfonic acid    [2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1261),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1262),-   3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzoic    acid (P-1266),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(3-morpholin-4-yl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1873),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(3-morpholin-4-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1878),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1879),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(6-morpholin-4-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1881),-   Propane-1-sulfonic acid    (2,4-difluoro-3-{5-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide    (P-1882),-   Propane-1-sulfonic acid    {3-[5-(4-cyano-3,5-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide    (P-1980),-   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide    (P-1996),-   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide    (P-1997),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1864),-   Propane-1-sulfonic acid    {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-4-fluoro-phenyl}-amide    (P-1432),-   4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide    (P-1546),-   4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-benzamide    (P-1547),-   Propane-1-sulfonic acid    (2,4-difluoro-3-{5-[4-(morpholine-4-carbonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide    (P-1548),-   3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide    (P-1549),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-2006),-   N-{2,4-Difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide    (P-2012),-   (3-Difluoromethoxy-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1528),-   N-{3-[3-(3-Difluoromethoxy-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1527),-   (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1558).-   N-{3-[3-(2,2-Difluoro-benzo[1,3]dioxole-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1564),-   3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine    (P-1529),-   N-(3-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl)-methanesulfonamide    (P-1530),-   (3,5-Bis-difluoromethoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1520),-   N-{3-[3-(3,5-Bis-difluoromethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1522),-   (2,2-Difluoro-benzo[1,3]dioxol-4-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1515),-   N-{3-[3-(2,2-Difluoro-benzo[1,3]dioxole-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1516),-   (2,6-Difluoro-3-methoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1387),-   (2,6-Difluoro-3-methoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1388),-   (2,6-Difluoro-3-methoxy-phenyl)-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1389),-   N-{3-[3-(2,6-Difluoro-3-methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1390),-   N-{3-[3-(2,6-Difluoro-3-methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1391),-   3-(2-Fluoro-3-methoxy-benzyl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine    (P-1323),-   3-(2-Fluoro-3-methoxy-benzyl)-5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine    (P-1324),-   3-(2-Fluoro-3-methoxy-benzyl)-5-(3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine    (P-1325),-   5-(3-Chloro-phenyl)-3-(2-fluoro-3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine    (P-1326),-   3-(2-Fluoro-3-methoxy-benzyl)-5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine    (P-1327),-   3-(2-Fluoro-3-methoxy-benzyl)-5-(3-trifluoromethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine    (P-1328),-   N-{3-[3-(2-Fluoro-3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1329),-   (2-Fluoro-3-methoxy-phenyl)-[5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone    (P-1330),-   (2-Fluoro-3-methoxy-phenyl)-[5-(3-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone    (P-1331),-   [5-(3-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-3-methoxy-phenyl)-methanone    (P-1332),-   [5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-3-methoxy-phenyl)-methanone    (P-1333),-   [5-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-3-methoxy-phenyl)-methanone    (P-1334),-   4-[3-(2-Fluoro-3-methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzonitrile    (P-1335),-   N-{3-[3-(2-Fluoro-3-methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1336),-   (2-Fluoro-3-methoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1338),-   (2-Fluoro-3-methoxy-phenyl)-[5-(4-trifluoromethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone    (P-1339),-   (2-Fluoro-3-methoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1343),-   (2-Fluoro-3-methoxy-phenyl)-[5-(3-trifluoromethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone    (P-1344),-   (5-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-trifluoromethoxy-phenyl)-methanone    (P-1408),-   (5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-trifluoromethoxy-phenyl)-methanone    (P-1413),-   N-{3-[3-(3-Trifluoromethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1428),-   N-{3-[3-(3-Trifluoromethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1422),-   (E)-3-{3-[3-(3-Trifluoromethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic    acid (P-1417),-   (3-Difluoromethoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1409),-   (3-Difluoromethoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1415),-   N-{3-[3-(3-Difluoromethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1430),-   N-{3-[3-(3-Difluoromethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1424),-   (E)-3-{3-[3-(3-Difluoromethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]1-phenyl}-acrylic    acid (P-1418),-   (3,5-Dimethoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1406),-   (3,5-Dimethoxy-phenyl)-(5-pyridin-3-yl)-methanone (P-1411),-   N-{3-[3-(3,5-Dimethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1426),-   N-{3-[3-(3,5-Dimethoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1420),-   (3-Fluoro-5-trifluoromethyl-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1407),-   (3-Fluoro-5-trifluoromethyl-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1412),-   N-{3-[3-(3-Fluoro-5-trifluoromethyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1427),-   N-{3-[3-(3-Fluoro-5-trifluoromethyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1421),-   (3,5-Dichloro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1414),-   N-{3-[3-(3,5-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1429),-   N-{3-[3-(3,5-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1423),-   (5-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-trifluoromethyl-phenyl)-methanone    (P-1405),-   (5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-trifluoromethyl-phenyl)-methanone    (P-1410),-   N-{3-[3-(3-Trifluoromethyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-1425),-   N-{3-[3-(3-Trifluoromethyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-1419), and-   (E)-3-{3-[3-(3-Trifluoromethyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic    acid (P-1416).    The following table indicates the 5-bromo azaindole (column 2) and    boronic acid (column 3) used to afford the compound (column 4).    Column 1 provides the compound number and column 5 the observed    mass.

MS(ESI) Boronic [M + H⁺]⁺ 5-Br azaindole acid Compound observed P-0082

406.2 P-0121

407.2 P-0079

411.1 P-0308

410.2 P-0156

503.2 P-0297

526.1 P-0228

453.1 P-0037

376.1 P-0008

411.1 P-0716

424.0 [M − H⁺]⁻ P-0700

429.1 P-0841

522.1 P-0734

445.0 P-0745

535.0 [M − H⁺]⁻ P-0746

519.2 [M − H⁺]⁻ P-0210

504.2 [M − H⁺]⁻ P-0721

469.0 P-0184

428.1 P-0685

491.1 P-0753

473.1 P-0636

456.1 P-0776

472.1 P-0956

490.1 P-0889

499.2 P-0877

486.3 P-0912

524.1 P-0874

484.3 [M − H⁺]⁻ P-0876

499.3 P-0897

438.3 P-1009

472.2 P-0027

334.1 P-0165

352.1 P-0857

455.1 [M − H⁺]⁻

P-1251

439.3 P-1259

474.2 P-1260

474.2 P-1261

490.2 P-1262

457.2 P-1266

500.1 P-1873

541.2 P-1878

555.3 P-1879

487.3 P-1881

542.3 P-1882

555.3 P-1980

509.2 P-1996

562.2 P-1997

512.2 P-1864

460.2 P-1432

472.2 P-1546

497.2 P-1547

527.3 P-1548

569.3 P-1549

499.3 P-2006

560.2 P-2012

632.1 P-1528

P-1527

P-1558

P-1564

P-1529

P-1530

P-1520

P-1522

P-1515

P-1516

P-1387

P-1388

P-1389

P-1390

P-1391

P-1323

P-1324

P-1325

P-1326

P-1327

P-1328

P-1329

P-1330

P-1331

P-1332

P-1333

P-1334

P-1335

P-1336

P-1338

P-1339

P-1343

P-1344

P-1408

P-1413

P-1428

P-1422

P-1417

P-1409

P-1415

P-1430

P-1424

P-1418

P-1406

P-1411

P-1426

P-1420

P-1407

P-1412

P-1427

P-1421

P-1414

P-1429

P-1423

P-1405

P-1410

P-1425

P-1419

P-1416

Example 4 Synthesis ofN-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ethanesulfonamideP-0728

Compound P-0728 was synthesized in eight steps from2,4-difluorophenylamine 42 as shown in Scheme 16.

Step 1—Preparation of dibenzyl-(2,4-difluoro-phenyl)-amine (52)

To 2,4-difluoro-phenylamine (42, 10.0 g, 77.4 mmol) inN,N-dimethylformamide (130 mL) were added potassium carbonate (32.1 g,0.23 mol) and benzyl bromide (21.2 mL, 0.18 mol). The reaction wasstirred at room temperature overnight. The reaction was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtrated. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 10% ethyl acetate in hexane. The appropriatefractions were combined and concentrated to provide the compound (52,12.0 g, 50%). MS (ESI) [M+H⁺]⁺=310.2.

Step 2—Preparation of 3-dibenzylamino-2,6-difluoro-benzaldehyde (53)

To dibenzyl-(2,4-difluoro-phenyl)-amine (52, 4.30 g, 13.9 mmol) intetrahydrofuran (60 mL), under an atmosphere of nitrogen, cooled in a−78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M inhexane, 6.1 mL, 15.3 mmol) slowly. The reaction was stirred for 1 hour,N,N-dimethylformamide (1.2 mL, 15.3 mmol) was added and the reaction wasallowed to warm to room temperature for 1 hour. The reaction was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 10% ethyl acetate in hexane to provide thecompound (53, 4.0 g, 85%). MS (ESI) [M+H⁺]⁻=337.2.

Step 3—Preparation of(3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(54)

To 3-dibenzylamino-2,6-difluoro-benzaldehyde (53, 0.76 g, 2.3 mmol) inmethanol (50 mL) were added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine(89, 0.40 g, 2.1 mmol, prepared as described in Example 17) andpotassium hydroxide (0.50 g, 8.9 mmol) under an atmosphere of nitrogen.The reaction was stirred at room temperature overnight. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated and purified by silica gel columnchromatography eluting with 5% methanol in methylene chloride to providethe compound (54, 0.60 g, 50%). MS (ESI) [M+H⁺]⁺=533.2.

Step 4—Preparation of(3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(55)

To(3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(54, 0.90 g, 1.7 mmol) in methylene chloride (20 mL) under an atmosphereof nitrogen was added Dess-Martin periodane (0.97 g, 2.3 mmol). Thereaction was stirred at room temperature for 15 minutes. The reactionwas poured into a solution of sodium bicarbonate and sodium thiosulfateand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated and purified by silica gel column chromatographyeluting with 5% methanol in methylene chloride to provide the compound(55, 0.70 g, 78%). MS (ESI) [M+H⁺]⁺=531.2.

Step 5—Preparation of(3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(56)

To(3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(55, 0.84 g, 1.6 mmol) in tetrahydrofuran (150 mL) was added sodiumhydride (210.0 mg, 60% in mineral oil, 5.3 mmol) under an atmosphere ofnitrogen. The reaction was stirred for 5 minutes. Triisopropylsilylchloride (0.80 mL, 3.8 mmol) was added and the reaction was stirred atroom temperature for 3 hours. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated and purified by silica gel column chromatographyeluting with 10% ethyl acetate in hexane to provide the compound (56,420 mg, 39%). MS (ESI) [M+H⁺]⁺=687.4.

Step 6—Preparation of(3-amino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(57)

To(3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(56, 55.0 mg, 0.080 mmol) in methanol (15 mL) was added 20% palladiumhydroxide on carbon (20 mg). The reaction was stirred under anatmosphere of hydrogen overnight. The reaction was filtered to removethe catalyst, and then concentrated to give the crude compound that wasused in the next step.

Step 7—Preparation ofN-[2,4-difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ethanesulfonamide(58)

To(3-amino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(57, 35.0 mg, 0.069 mmol) in methylene chloride (6 mL) was addedmethanesulfonyl chloride (0.30 mL, 3.9 mmol) and triethylamine (0.40 mL,2.9 mmol). The reaction was stirred at room temperature overnight. Thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentratedto give the crude compound that was used in the next step.

Step 8—Preparation ofN-[2,4-difluoro-3-(5-pyridin-3-yl-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ethanesulfonamide(P-0728)

ToN-[2,4-difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ethanesulfonamide(58, 35.0 mg, 0.060 mmol) in tetrahydrofuran (10 mL) was addedtetra-n-butylammonium fluoride (19 mg, 0.072 mmol). The reaction wasstirred at room temperature for 5 minutes. The reaction was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 5% methanol in methylene chloride to providethe compound (P-0728, 5.6 mg, 22%). MS (ESI) [M+H⁺]⁺=443.1\

Also,(3-Benzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0807 and(3-amino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0763

were synthesized by reacting(3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(56, 20.0 mg, 0.033 mmol) and(3-Amino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(57, 20.0 mg, 0.039 mmol), respectively, in tetrahydrofuran (5.0 mL)with tetra-n-butylammonium fluoride (13 mg, 0.050 mmol). The reactionmixtures were stirred at room temperature for 10 minutes, poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and concentrated. Theproducts were isolated by silica gel column chromatography eluting with10% ethyl acetate in hexane to give P-0807 (2.0 mg, MS (ESI)[M+H⁺]⁺=441.1) and P-0763 (1.7 mg, MS (ESI) [M−H⁺]⁻=351.1) as whitesolids.

Example 5 Preparation of propane-2-sulfonic acid[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0850

Compound P-0850 was synthesized in four steps from2,4-difluorophenylamine 42 as shown in Scheme 17.

Step 1—Preparation of propane-2-sulfonic acid(2,4-difluoro-phenyl)-amide (59)

To 2,4-difluoro-phenylamine (42, 4.0 mL, 40.0 mmol) in methylenechloride (50 mL) were added pyridine (3.37 mL, 42.3 mmol),propane-2-sulfonyl chloride (6.00 g, 42.3 mmol) anddimethylaminopyridine (0.20 g, 1.64 mmol) under an atmosphere ofnitrogen. The reaction was stirred at 45° C. overnight. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated and purified by silica gel columnchromatography 3% methanol in methylene chloride to give a white solid(59, 8.0 g, 85%). MS (ESI) [M−H⁺]⁻=234.0.

Step 2—Preparation of propane-2-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (60)

To propane-2-sulfonic acid (2,4-difluoro-phenyl)-amide (59, 2.35 g, 9.95mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooledwith a dry ice/acetone bath was added 1.60 M of n-butyllithium (1.60 Min hexane, 6.53 mL, 10.45 mmol). The reaction was stirred for 40minutes, and then another portion of n-butyllithium (1.60 M in hexane,6.84 mL, 10.94 mmol). The reaction was stirred for 1 hour andN,N-dimethylformamide (0.92 mL, 11.9 mmol) was added. The reaction wasallowed to warm to room temperature overnight. The reaction was pouredinto water extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtrated. Thefiltrate was concentrated and purified by silica gel columnchromatography (dichloromethane/methanol 5%) to give the compound (60,1.4 g, 53.4%). MS (ESI) [M−H⁺]⁻=263.4.

Step 3—Preparation of propane-2-sulfonic acid{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide(61)

To propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (60,220.0 mg, 0.83 mmol) in methanol (15 mL) was added5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 150.0 mg, 0.77 mmol,prepared as described in Example 17) and potassium hydroxide (537.0 mg,9.6 mmol) under an atmosphere of nitrogen. The reaction was stirred atroom temperature overnight. The reaction was poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate and filtrated. The filtrate was concentratedand purified by silica gel column chromatography eluting with 5%methanol in dichloromethane to give the compound (61, 160 mg, 45.3%). Inthis step, minor compound Propane-2-sulfonic acid{2,4-difluoro-3-[methoxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amidewas also formed and isolated. MS (ESI) [M+H⁺]⁺=460.1.

Step 4—Preparation of propane-2-sulfonic acid[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide(P-0850)

To propane-2-sulfonic acid{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide(61, 40.0 mg, 0.087 mmol) in tetrahydrofuran (10 mL) was addedDess-Martin periodane (48.0 mg, 0.11 mmol). The reaction was stirred atroom temperature for 5 minutes. The reaction was poured into sodiumthiosulfate and potassium carbonate solution and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and filtrated. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 5% methanol inmethylene chloride to give the compound (P-0850, 13.4 mg, 33.5%). MS(ESI) [M+H⁺]⁺=458.1.

N-(2,4-Difluoro-3-formyl-phenyl)-3-trifluoromethyl-benzenesulfonamide579,N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide580, and N-(2,4-difluoro-3-formyl-phenyl)-4-fluoro-benzenesulfonamide581, and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester

were prepared following Steps 1 and 2 of Scheme 17, substitutingpropane-2-sulfonyl chloride with 3-trifluoromethyl-benzenesulfonylchloride, 4-trifluoromethyl-benzenesulfonyl chloride,4-fluoro-benzenesulfonyl chloride, and benzyl chloroformate,respectively, in Step 1.

Propane-1-sulfonic acid[4-chloro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amideP-1004

was prepared using the protocol of Scheme 17, substituting2,4-difluoro-phenylamine with 4-chloro-2-fluoro-phenylamine andpropane-2-sulfonyl chloride with propane-1-sulfonyl chloride in Step 1,and 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with5-chloro-7-azaindole 80 (see Example 9) in Step 3. MS (ESI)[M+H⁺]⁺=430.1.

Propane-1-sulfonic acid[4-chloro-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0904

was prepared using the protocol of Scheme 17, substituting2,4-difluoro-phenylamine with 4-chloro-2-fluoro-phenylamine andpropane-2-sulfonyl chloride with propane-1-sulfonyl chloride in Step 1,and 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with 7-azaindole 94 inStep 3. MS (ESI) [M+H⁺]⁺=396.2.

[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-carbamicacid methyl ester P-0974 and[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-carbamicacid benzyl ester P-0894

were prepared using the protocol of Scheme 17, substitutingpropane-2-sulfonyl chloride with benzyl chloroformate in Step 1 and5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with 7-azaindole in Step 3.The products of Step 3 were a mixture of{2,4-Difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid methyl ester and{2,4-Difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid benzyl ester that were separated by silica gel columnchromatography and carried through Step 4 separately to provide P-0974and P-0894, respectively. P-0974 MS (ESI) [M−H⁺]⁻=330.1. P-0894 MS (ESI)[M−H⁺]⁺=406.1.

[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-carbamicacid methyl ester P-0486 and[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-carbamicacid benzyl ester P-0302

were prepared using the protocol of Scheme 17, substitutingpropane-2-sulfonyl chloride with benzyl chloroformate in Step 1. Theproducts of Step 3 were a mixture of{2,4-Difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid methyl ester and{2,4-Difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid benzyl ester that were separated by silica gel columnchromatography and carried through Step 4 separately to provide P-0486and P-0302, respectively. P-0486 MS (ESI) [M+H⁺]⁺=409.1. P-0302 MS (ESI)[M+H⁺]⁺=485.1.

[5-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,3,6-trifluoro-phenyl)-methanoneP-0102

was prepared using the protocol of Steps 3 and 4 of Scheme 17,substituting propane-2-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide with 2,3,6-Trifluoro-benzaldehydeand 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine in Step 3. MS(ESI) [M−H⁺]⁻=429.0.

Thiophene-2-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amideP-1267

was prepared using the protocol of Steps 3 and 4 of Scheme 17,substituting 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with5-chloro-7-azaindole 80 (see Example 9) and propane-2-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 60 with thiophene-2-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 512 (see Example 21) in Step 3. MS(ESI) [M+H⁻]⁻=451.9.

Thiophene-3-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amideP-1268

was prepared using the protocol of Steps 3 and 4 of Scheme 17,substituting 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with5-chloro-7-azaindole 80 (see Example 9) and propane-2-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 60 with thiophene-3-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 513 (see Example 21) in Step 3. MS(ESI) [M+H⁺]⁺=454.1.

Additional compounds were prepared following the protocol of Scheme 17,optionally replacing propane-2-sulfonyl chloride with an appropriateacid chloride in Step 1 and or 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridinewith an appropriate azaindole in Step 3. Azaindoles were purchased orsynthesized as described in Examples 6, 13, 14, 16 and 17. Somecompounds were isolated after Step 3, as either hydroxy or methoxyderivatives. The following compounds were made following this procedure:

-   Dimethylamine-1-sulfonic acid    {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide    (P-1257),-   N-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide    (P-0798),-   Propane-1-sulfonic acid    [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-0773),-   Dimethylamine-1-sulfonic acid    [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-0898),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide    (P-0885),-   N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-0902),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[hydroxy-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-1239),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0991),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-1240),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[methoxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-1241),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[hydroxy-(5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-1242),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0997),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[hydroxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-1243),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[methoxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-1244),-   Propane-1-sulfonic acid    (2,4-difluoro-3-{hydroxy-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-phenyl)-amide    (P-1245),-   Propane-1-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-0933),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0907),-   Piperidine-1-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1020),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methoxy-benzenesulfonamide    (P-0983),-   N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide    (P-0954),-   N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-acetamide    (P-1002),-   Dimethylamine-1-sulfonic acid    [3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-0950),-   Dimethylamine-1-sulfonic acid    [3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-0837),-   Dimethylamine-1-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1258),-   Butane-1-sulfonic acid    [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1263),-   Butane-1-sulfonic acid    [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1264),-   Butane-1-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1265),-   Propane-1-sulfonic acid    [3-(5-ethoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1252),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide    (P-1253),-   Propane-1-sulfonic acid    {3-[5-(2-diethylamino-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide    (P-1254),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-ethyl-benzenesulfonamide    (P-1700),-   N-[3-(5-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-1783),-   Thiophene-3-sulfonic acid    [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1798),-   Benzo[b]thiophene-2-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1799),-   5-Pyridin-2-yl-thiophene-2-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1800),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-cyano-benzenesulfonamide    (P-1822),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-4-methyl-benzenesulfonamide    (P-1823),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropyl-benzenesulfonamide    (P-1839),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide    (P-1840),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-difluoro-benzenesulfonamide    (P-1841),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methyl-benzenesulfonamide    (P-1842),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-oxazol-5-yl-benzenesulfonamide    (P-1843),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide    (P-1865),-   N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide    (P-1871),-   N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide    (P-1872),-   Propane-1-sulfonic acid    (2,4-difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide    (P-1998),-   N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide    (P-2005), and-   N-(2,4-Difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-4-trifluoromethyl-benzenesulfonamide    (P-2013).    The following table indicates the acid chloride (column 2) and the    azaindole (column 3) used to afford the target compounds (column 4).    Column 1 provides the compound number and column 5 the observed    mass. Compounds isolated after Step 3 of Scheme 17 are so noted in    column 1.

MS(ESI) Sulfonyl [M + H⁺]⁺ chloride Azaindole Compound observed P-1257

415.1 P-0798

489.9 491.1 [M − H⁺]⁻ P-0773

455.9 457.9 [M − H⁺]⁻ P-0898

497.0 499.1 P-0885

446.1 448.1 [M − H⁺]⁻ P-0902

430.1 [M − H⁺]⁻ P-1239 Step 3

422.2 [M − H⁺]⁻ P-0991

420.2 P-1240 Step 3

396.4 [M − H⁺]⁻ P-1241 Step 3

410.3 [M − H⁺]⁻ P-1242 Step 3

424.3 [M − H⁺]⁻ P-0997

422.3 P-1243 Step 3

412.3 [M − H⁺]⁻ P-1244 Step 3

426.4 [M − H⁺]⁻ P-1245 Step 3

480.3 [M − H⁺]⁻ P-0933

414.2 P-0907

396.1 [M − H⁺]⁻ P-1020

455.2 P-0983

476.1 [M − H⁺]⁻ P-0954

448.2 P-1002

393.2 P-0950

381.2 P-0837

458.1 P-1258

415.1 P-1263

472.1 474.1 P-1264

424.2 P-1265

426.0 [M − H⁺]⁻ P-1252

424.2 P-1253

454.2 P-1254

495.3 P-1700

476.2 P-1783

510   P-1798

495.9 497.6 [M − H⁺]⁻ P-1799

502.0 (-) P-1800

531.1 P-1822

473.1 P-1823

480.1 P-1839

488   P-1840

464   P-1841

482   P-1842

460.0 [M − H⁺]⁻ P-1843

513.0 [M − H⁺]⁻ P-1865

432.1 P-1871

506.2 P-1872

506.2

P-1998

530.3 P-2005

556.0 P-2013

539.2

Example 6 Synthesis of propane-1-sulfonic acid[2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0848 and Related Compounds

Propane-1-sulfonic acid[2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0848 was synthesized in five steps from 5-bromo-7-azaindole 67 asshown in Scheme 18.

Step 1—Preparation of5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68)

To 5-bromo-7-azaindole (67, 1.5 g, 7.6 mmol) in N,N-dimethylformamide(20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0mmol) and triisopropylsilyl chloride (2.6 mL, 12.0 mmol), under anatmosphere of nitrogen. The reaction was stirred for 2 hours at roomtemperature. The reaction was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 10% ethyl acetate inhexane to give the compound (68, 1.6 g, 59%). MS (ESI) [M+H⁺]⁺=352.3.

Step 2—Preparation of5-phenyl-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-amine(69)

To 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68, 0.10 g,0.3 mmol) in toluene (5 mL) were added aniline (0.04 mL, 0.42 mmol),sodium tert-butoxide (0.15 g, 1.56 mmol),tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol) and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.01 mmol).The reaction was heated to 160° C. for 10 minutes in a CEM Discovermicrowave instrument. The reaction was concentrated and purified bysilica gel column chromatography eluting with 3% ethyl acetate in hexaneto give the compound (69, 40 mg, 40%). MS (ESI) [M+H⁺]⁺=366.6.

Step 3—Preparation of phenyl-(-1H-pyrrolo[2,3-b]pyridine-5-yl)-amine(70)

To 5-phenyl-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-amine(69, 0.14 g, mmol) in tetrahydrofuran (3.0 mL) was addedtetra-n-butylammonium fluoride (0.197 g, 0.76 mmol). The reaction wasstirred for 1 hour at room temperature. The reaction was concentratedand purified by silica gel column chromatography eluting with 3% ethylacetate in hexane to give the compound (70, 60 mg, 76%). MS (ESI)[M+H⁺]⁺=210.3.

Step 4—Preparation of propane-1-sulfonic acid{2,4-difluoro-3-[hydroxy-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide(71)

To phenyl-(-1H-pyrrolo[2,3-b]pyridine-5-yl)-amine (70, 17.0 mg, 0.09mmol) in methanol (5.0 mL) were added potassium hydroxide (92.0 mg, 1.6mmol) and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide(73, 19.0 mg, 0.072 mmol, prepared as described in Example 7) under anatmosphere of nitrogen. The reaction was stirred for 12 hours at roomtemperature. The reaction was concentrated and purified by silica gelcolumn chromatography eluting with 1% methanol in dichloromethane togive the compound (71, 17 mg, 50%). MS (ESI) [M+H⁺]⁺=473.5.

Step 5—Preparation of propane-1-sulfonic acid[2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide(P-0848)

To propane-1-sulfonic acid{2,4-difluoro-3-[hydroxy-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide(71, 7.5 mg, 0.016 mmol) in tetrahydrofuran (3 mL) was added Dess-Martinperiodane (6.70 mg, 0.0158 mmol) under an atmosphere of nitrogen. Thereaction was stirred for 20 minutes. The reaction was concentrated andpurified by silica gel column chromatography eluting with 1% methanol indichloromethane to give the compound (P-0848, 6.2 mg, 84%). MS (ESI)[M+H⁺]⁺=471.2.

Propane-1-sulfonic acid[2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-0853, propane-1-sulfonic acid{2,4-difluoro-3-[5-(4-methyl-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amideP-0860, and propane-1-sulfonic acid{2,4-difluoro-3-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide

respectively,were prepared using the protocol of Scheme 18, substituting aniline withmorpholine, 4-methyl-piperidine, and 4-methyl-piperazine, respectively,in Step 2. P-0853 MS (ESI) [M+H⁺]⁺=465.2. P-0860 MS (ESI) [M+H⁺]⁺=477.3.P-1246 MS (ESI) [M−H⁺]⁻=478.4.

4-[5-(3-Chloro-4-methoxy-phenylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylicacid butylamide P-1859

was prepared using the protocol of Scheme 18, substituting aniline with3-chloro-4-methoxy-phenylamine in Step 2 and propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 73 with4-Formyl-indole-1-carboxylic acid butylamide 519 (see Example 22) inStep 4. MS (ESI) [M+H⁺]⁺=516.2.

(1H-Indol-4-yl)-[5-(4-morpholin-4-yl-phenylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanoneP-1792,[5-(4-Chloro-phenylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(1H-indol-4-yl)-methanoneP-1793,(1H-Indol-4-yl)-[5-(4-piperidin-1-yl-phenylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanoneP-1794, and[5-(3-Chloro-4-methoxy-phenylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(1H-indol-4-yl)-methanoneP-1795,

respectively,were prepared using the protocol of Steps 1-3 of Scheme 18, substituting5-bromo-7-azaindole with4-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylicacid butylamide (P-1687, prepared as described in Example 22, Scheme 41)in Step 1 and replacing aniline with 4-morpholin-4-yl-phenylamine,4-chloro-phenylamine, 4-piperidin-1-yl-phenylamine, and3-chloro-4-methoxy-phenylamine, respectively, in Step 2. P-1792 MS (ESI)[M+H⁺]⁺=438.3. P-1793 MS (ESI) [M+H⁺]⁺=387.1. P-1794 MS (ESI)[M+H⁺]⁻=436.3. P-1795 MS (ESI) [M+H⁺]⁺=417.1.

Example 7 Synthesis of propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 73

Compound 73 was synthesized in two steps from 2,4-difluorophenylamine 42as shown in Scheme 19,

Step 1—Preparation of Propane-1-sulfonic acid(2,4-difluoro-phenyl)-amide (72)

To 2,4-difluoro-phenylamine (42, 3.0 mL, 29.8 mmol) in tetrahydrofuran(50 mL) were added triethylamine (9.13 mL, 65.5 mmol) andpropane-1-sulfonyl chloride (2.90 mL, 25.8 mmol) under an atmosphere ofnitrogen. The reaction was stirred at room temperature overnight. Thereaction was poured into 1 M HCl and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated to give the compound (72,2.0 g, 28%) that was used in the next step.

Step 2—Preparation of propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (73)

To propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (72, 1.5 g, 6.38mmol) in tetrahydrofuran (10 mL) under an atmosphere of nitrogen, cooledin a −78° C. acetone/dry ice bath was added lithium diisopropylamide(0.80 M in tetrahydrofuran, 24 mL, freshly prepared from n-butyllithiumand diisopropylamine). After 30 minutes, N,N-dimethyl-formamide (542 μL,7.018 mmol) was added dropwise to the reaction. The reaction was stirredfor 30 minutes at −78° C. and then allowed to warm to room temperaturefor 40 minutes. The reaction was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 5% ethylacetate in hexane to give a light yellow solid (73, 300 mg, 18%). MS(ESI) [M−H⁺]⁻=262.3.

Example 8 Synthesis of propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1116

Compound P-1116 was synthesized in four steps from 3-amino-benzoic acidethyl ester 74 as shown in Scheme 20.

Step 1—Preparation of 3-(propane-1-sulfonylamino)-benzoic acid ethylester (75)

To 3-amino-benzoic acid ethyl ester (74, 5.0 g, 0.030 mol) in methylenechloride (30.0 mL) were added pyridine (3.67 mL, 0.045 mol) andpropane-1-sulfonyl chloride (3.75 mL, 33.0 mmol). The reaction wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate and concentrated.The desired compound was isolated by silica gel column chromatographyeluting with 20% ethyl acetate in hexane to give a white solid (75, 6.0g, 74.1%).

Step 2—Preparation of 3-(propane-1-sulfonylamino)-benzoic acid (76)

To 3-(propane-1-sulfonylamino)-benzoic acid ethyl ester (75, 1.60 g,5.90 mmol) in water was added lithium hydroxide (1.0 g, 4.2 mmol) andtetrahydrofuran (20 mL). The reaction was stirred at room temperatureovernight. The reaction mixture was acidified with 1 N HCl, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and washedwith ethyl acetate to give the compound (76, 1.2 g, 84.5%) as whitesolid. MS (ESI) [M−H⁺]⁺=242.1.

Step 3—Preparation of 3-(propane-1-sulfonylamino)-benzoyl chloride (77)

A solution of 3-(propane-1-sulfonylamino)-benzoic acid (76, 1.20 g, 4.93mmol) in thionyl chloride was heated to reflux for 3.0 hours.Evaporation of the solvent gave compound 77 as white solid that was usedfor the next step.

Step 4—Preparation of propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1116)

To aluminum trichloride (4.8 g, 36.0 mmol) in methylene chloride (70.0mL), under an atmosphere of nitrogen, was added5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 797 mg, 4.04 mmol) dissolved inmethylene chloride (5.0 mL). The reaction was stirred at roomtemperature for 30 minutes, followed by addition of3-(propane-1-sulfonylamino)-benzoyl chloride (77, 1.10 g, 4.20 mmol)dissolved in methylene dichloride (4.0 mL). The reaction was stirred atroom temperature for 2 hours. The reaction was poured into water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 30% ethyl acetate inhexane to give a white solid (P-1116, 300.0 mg). MS (ESI) [M−H⁺]⁻=420.1,422.1.

Example 9 Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine 80

Compound 80 was synthesized in two steps from5-bromo-1-triisopropylsilyl-7-azaindole 68 as shown in Scheme 21.

Step 1—Preparation5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (79)

To 5-bromo-1-triisopropylsilyl-7-azaindole (68, 1.60 g, 4.53 mmol,prepared as described in Example 6) in tetrahydrofuran (50.0 mL), underan atmosphere of nitrogen at −78° C., was added tert-butyllithium (1.70M in hexane, 6.12 mL). The reaction was stirred for 1 hour, followed byaddition of hexachloroethane (1.29 g, 5.43 mmol). The reaction wasstirred for 3 hours, poured into water, and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated to give the crude compound (79,1.60 g). MS (ESI) [M+H⁺]⁺=309.3.

Step 2—Preparation 5-chloro-1H-pyrrolo[2,3-b]pyridine (80)

To 5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (79, 1.40 g,4.53 mmol) in tetrahydrofuran (15 mL) was added tetr-n-butylammoniumfluoride (1.42 g, 5.43 mmol). The reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was concentrated andisolated by silica gel column chromatography eluting with 30% ethylacetate in hexane to give the compound (80, 0.40 g, 58% over 2 steps).MS (ESI) [M−H⁺]⁻=153.1.

5-Fluoro-1H-pyrrolo[2,3-b]pyridine 81

was prepared using the protocol of Scheme 21, substitutinghexachloroethane with N-fluoro-N-(phenylsulfonyl)benzenesulfonamide inStep 1. MS (ESI) [M+H⁺]⁺=137.1.

Example 10 Synthesis of2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenolP-0078 and Related Compounds

Compound P-0078 was synthesized in two steps from5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 as shown in Scheme 24.

Step 1—Preparation of2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol(P-0009)

To carbonic acid tert-butyl ester 2,4-difluoro-3-formyl-phenyl ester(39, 0.405 g, 15.7 mmol) in methanol (36 mL), under an atmosphere ofnitrogen, was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 288.0mg, 14.8 mmol, prepared as described in Example 17) and potassiumhydroxide (145.0 mg, 25.9 mmol). The reaction was stirred at roomtemperature overnight. Then, the reaction was poured into water, andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated. The mixture waspurified by silica gel column chromatography eluting with 4% methanol inmethylene chloride to provide two separate compounds, a colorless oil(P-0009, 0.23 g, 44.1%, MS (ESI) [M+H⁺]⁺=354.1), and a colorless oil(P-0042, 0.050 g, 9,2%, MS (ESI) [M+H⁺]⁺=367.1).

Step 2—Preparation of2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol(P-0078)

To2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol(P-0009, 34.0 mg, 0.096 mmol) in acetonitrile (15 mL), were addedtrifluoroacetic acid (1.0 mL, 13.0 mmol) and triethylsilane (2.0 mL,12.0 mmol). The reaction was stirred at room temperature for 48 hours.The reaction mixture was poured sodium bicarbonate solution, andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 30% ethyl acetate in hexane to give the compound (P-0078, 6.0 mg,19%). MS (ESI) [M+H⁺]⁺=338.1.

Additional compounds were prepared following the protocol of Scheme 24,replacing either or both of carbonic acid tert-butyl ester2,4-difluoro-3-formyl-phenyl ester 39 with an appropriate aldehydeand/or 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with an appropriateazaindole in Step 1. Azaindoles were purchased or synthesized asdescribed in Examples 6 and 17. Aldehydes were prepared as described inExample 5 (through Step 2). Some compounds were isolated after Step 1,as either hydroxy or methoxy derivatives. The following compounds weremade following this procedure:

-   3-[(5-Bromo-1-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-2,4-difluoro-phenol    (P-0126),-   3-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenol    (P-1180),-   3-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenol    (P-0122),-   {2,4-Difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methyl]-phenyl}-carbamic    acid benzyl ester (P-0095),-   [2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-carbamic    acid benzyl ester (P-0396),-   {2,4-Difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamic    acid methyl ester (P-0065),-   [2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-carbamic    acid methyl ester (P-0257),-   Propane-2-sulfonic acid    {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-2,4-difluoro-phenyl}-amide    (P-0356),-   Propane-2-sulfonic acid    [3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-amide    (P-0867),-   Propane-2-sulfonic acid    {2,4-difluoro-3-[methoxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-0947),-   Propane-1-sulfonic acid    {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-amide    (P-0188),-   Propane-1-sulfonic acid    [3-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-amide    (P-0910),-   Dimethylamino-1-sulfonic acid    {2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide    (P-0944),-   3-(2-Fluoro-3-methoxy-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine    (P-0269),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide    (P-0818),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide    (P-0911),-   Propane-1-sulfonic acid    [2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide    (P-0964),-   Propane-1-sulfonic acid    {2,4-difluoro-3-[5-(4-methyl-piperidin-1H-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenyl}-amide    (P-0984),-   {3-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-carbamic    acid tert-butyl ester (P-0318),-   {3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-carbamic    acid methyl ester,-   {2,4-Difluoro-3-[hydroxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamic    acid methyl ester, and-   {2,4-Difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamic    acid methyl ester,-   5-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-1H-pyrrolo[2,3-b]pyridine    (P-1474), and-   5-Bromo-3-(2-fluoro-3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine    (P-0535).    The following table indicates the aldehyde (column 2) and azaindole    (column 3) used to afford the target compound (column 4). Column 1    provides the compound number and column 5 the observed mass.    Compounds isolated after Step 1 of Scheme 24 are so noted in column    1.

MS(ESI) [M + H⁺]⁺ Aldehyde Azaindole Compound observed P-0126 Step 1

369.1 371.1 P-1180 Step 1

353.0 355.0 P-0122

339.0 341.0 P-0095 P-0065 Step 1*

 

P-0396

471.2 P-0257

395.1 P-0356 Step 1

474.1 476.1 P-0867

460.2 P-0947 Step 1

459.2 P-0188 Step 1

460   462   P-0910

441.1 446.1 P-0944 Step 1

460.2 P-0269

334.2 P-0818

457.1 P-0911

442.2 P-0964

449.3 [M − H⁺]⁻ P-0984

463.3 P-0318 Step 1

454.1 456.1 Isolated Step 1

Isolated Step 1

Isolated Step 1

Isolated Step 1

P-1474

345.1 347.1 P-0535

335.1 337.1 *P-0095 and P-0065 were both produced in Step 1 and isolatedfrom the mixture. These were carried through to step 2 to provide P-0396and P-0257, respectively.

Example 11 Synthesis ofN-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]-3-methoxy-benzenesulfonamideP-0971

Compound P-0971 was synthesized in four steps from2,4-difluorophenylamine 42 as shown in Scheme 26.

Step 1—Preparation ofN-(2,4-difluoro-phenyl)-3-methoxy-benzenesulfonamide (91)

To 2,4-difluoro-phenylamine(42, 0.44 mL, 4.4 mmol) in methylene chloride(10.0 mL), under an atmosphere of nitrogen, were added pyridine (1.00mL, 12.4 mmol) and 3-methoxy-benzenesulfonyl chloride (1.00 g, 4.84mmol). After 12 hours, the reaction was poured into cold 1 M HCl andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% ethyl acetate in hexane to give light yellow solid (91, 0.90 g,69%). MS (ESI) [M+H⁺]⁺=300.

Step 2—Preparation ofN-{2,4-difluoro-3-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-3-methoxy-benzenesulfonamide(92)

To N-(2,4-difluoro-phenyl)-3-methoxy-benzenesulfonamide (91, 0.148 g,0.494 mmol) in tetrahydrofuran (10.0 mL) cooled in a −78° C. acetone/dryice bath, under an atmosphere of nitrogen, was added lithiumdiisopropylamide (0.85 M in tetrahydrofuran, 1.45 mL, 1.23 mmol)dropwise. After 30 minutes,1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (96, 0.15g, 0.500 mmol, prepared as described in Example 12) was added intetrahydrofuran (2.0 mL) into the reaction dropwise. Then the reactionwas stirred for 1 hour at −78° C. and allowed to reach room temperature.The reaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 40% ethyl acetate in hexane to givelight yellow solid (92, 0.080 g, 26.8%). MS (ESI) [M+H⁺]⁺=602.

Step 3—Preparation ofN-{2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-phenyl}-3-methoxy-benzenesulfonamide(93)

ToN-{2,4-difluoro-3-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-3-methoxy-benzenesulfonamide(92, 0.075 g, 0.12 mmol) in tetrahydrofuran (3.0 mL), was addedtetra-n-butylammonium fluoride (0.039 g, 0.15 mmol). The reaction wasstirred at room temperature for 20 minutes. The reaction was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 3% methanol in dichloromethane to give lightyellow solid (93, 0.030 g, 55%). MS (ESI) [M+H⁺]⁺=446.

Step 4—Preparation ofN-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]-3-methoxy-benzenesulfonamide(P-0971)

ToN-{2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-phenyl}-3-methoxy-benzenesulfonamide(93, 0.02 g, 0.05 mmol) in tetrahydrofuran (3.0 mL) was addedDess-Martin periodane (0.02 g, 0.015 mmol) under an atmosphere ofnitrogen. The reaction was stirred for 10 minutes at room temperature.The reaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 3% methanol in dichloromethane togive light yellow solid (P-0971, 0.010 g, 50%). MS (ESI) [M+H⁺]⁺=444.

Additional compounds were prepared following the protocol of Scheme 26,replacing 3-methoxy-benzene sulfonyl chloride with the appropriatesulfonyl chloride in Step 1. The following compounds were made followingthis procedure:

-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-dimethoxy-benzenesulfonamide    (P-1131),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide    (P-0958),-   Piperidine-1-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-0952),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-0931),-   4-Butoxy-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-1006),-   4-Chloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-0937),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3,4-dimethoxy-benzenesulfonamide,    (P-1090), and-   3,4-Dichloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-1015).    The following table indicates the sulfonyl chloride (column 2) used    to afford the target compound (column 3). Column 1 provides the    compound number and column 4 gives the observed mass.

MS(ESI) [M + H⁺]⁺ Sulfonyl chloride Compound observed P-1131

474.2 P-0958

444.2 P-0952

421.2 P-0931

482.2 P-1006

486.2 P-0937

446.1 [M − H⁺]⁻ P-1090

474.2 P-1015

480.0 482.1 [M − H⁺]⁻ * Piperidine-1-sulfonyl chloride prepared fromsulfuryl chloride and piperidine in acetonitrile, refluxed for 8 hours,concentrated, and used without further purification.

Example 12 Synthesis of1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde 96

Compound 96 was synthesized in two steps from 7-azaindole 94 asdescribed in Scheme 27.

Step 1—Preparation of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (95)

To 1H-Pyrrolo[2,3-b]pyridine (94, 16.0 g, 135 mmol) in water (110 mL),were added hexamethylenetetramine (26.0 g, 185 mmol), and acetic acid(55.0 mL, 967 mmol). The reaction was refluxed for 12 hours. Water (329mL) was added and the reaction was cooled to room temperature. Thereaction was filtrated and washed with water to give the compound (95,15.0 g, 76%). MS (ESI) [M+H⁺]⁺=147.

Step 2—Preparation of1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (96)

To 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (95, 4.05 g, 27.71 mmol) intetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil,1.5 g, 38 mmol) and triisopropylsilyl chloride (8.0 mL, 38 mmol) underan atmosphere of nitrogen. The reaction was stirred for 2 hours at roomtemperature. The reaction was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 10% ethyl acetate inhexane to give the compound (96, 3.0 g, 36%). MS (ESI) [M+H⁺]⁺=303.

Example 13 Synthesis of 5-isopropyl-1H-pyrrolo[2,3-b]pyridine 99

Compound 98 was synthesized in three steps from5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 68 described inScheme 28.

Step 1—Preparation of2-(1-triisopropylsilanol-1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-2-ol (97)

To 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68, 2.0 g,5.66 mmol, prepared as described in Example 6) in tetrahydrofuran (20.0mL), cooled in a −78° C. acetone dry ice bath, under an atmosphere ofnitrogen, was added tert-butyllithium (1.7 M in tetrahydrofuran, 7.3 mL,12 mmol) dropwise. After 20 minutes, acetone (0.830 mL, 11 mmol) wasadded dropwise to the reaction. The reaction was stirred for 30 minutesat −78° C. and then allowed to reach room temperature. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated and purified by silica gel columnchromatography eluting with 10% ethyl acetate in hexane to give thecompound (97, 1.30 g, 69%). MS (ESI) [M+H⁺]⁺=333.

Step 2—Preparation of 5-isopropenyl-1H-pyrrolo[2,3-b]pyridine (98)

To 2-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-2-ol(97, 0.500 g, 1.5 mmol) in acetonitrile (10.0 mL) were addedtriethylsilane (1.00 mL, 6.3 mmol) and trifluoroacetic acid (0.50 mL,6.5 mmol) under an atmosphere of nitrogen. The reaction was refluxed for3 hours, then cooled down to room temperature. The reaction was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 50% ethyl acetate in hexane to give thecompound (98, 0.200 g, 84%). MS (ESI) [M+H⁺]⁺=159.

Step 3—Preparation of 5-isopropyl-1H-pyrrolo[2,3-b]pyridine (99)

To 5-isopropenyl-1H-pyrrolo[2,3-b]pyridine (98, 0.080 g, 0.501 mmol) intetrahydrofuran (5.0 mL) was added 20% palladium hydroxide on carbon(5.0 mg). The reaction was stirred under hydrogen at 40 psi for 30minutes. The reaction mixture was filtered and concentrated to give thecompound (99, 0.078 g, 96%). MS (ESI) [M+H⁺]⁺=161.

Example 14 Synthesis of 5-Methyl-1H-pyrrolo[2,3-b]pyridine 101

Compound 101 was synthesized in two steps from5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 68 described inScheme 29.

Step 1—Preparation of5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (100)

To PdCl₂(dppf) (0.04 g, 0.05 mmol) in toluene (10.0 mL) under anatmosphere of nitrogen were added5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68, 0.3 g, 0.8mmol, prepared as described in Example 6, 1.0 ml in toluene) andmethylmagnesium bromide (1.0 M in tetrahydrofuran, 3.0 mL, 3.0 mmol).The reaction was stirred 90° C. for 2 hours and then allowed to reach toroom temperature. The reaction was poured into citric acid (0.1 M inwater) and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 50% ethyl acetate in hexane to give thecompound (100, 0.16 g, 60.0%). MS (ESI) [M+H⁺]⁺=289.4.

Step 2—Preparation of 5-Methyl-1H-pyrrolo[2,3-b]pyridine (101)

To 5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (100, 0.160g, 0.55 mmol) in tetrahydrofuran (3.0 mL) was addedtetra-n-butylammonium fluoride (0.145 g, 0.55 mmol). The reaction wasstirred for 1 hour at room temperature. The reaction was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 3% methanol in dichloromethane to providelight yellow solid (101, 0.07 g, 95%).

MS (ESI) [M+H⁺]⁺=133.2.

Methyl-1H-pyrrolo[2,3-b]pyridine

was prepared following the protocol of Scheme 29, substitutingmethylmagnesium bromide with ethylmagnesium bromide in Step 1.

Example 15 Synthesis of1-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-propyl-ureaP-0774 and Related Compounds

Compound P-0774 was synthesized in two steps from{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methyl]-phenyl}-carbamic acid methyl ester P-0065described in Scheme 30.

Step 1—Preparation of1-{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methyl]-phenyl}-3-propyl-urea(103)

To{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid methyl ester (P-0065, 30.0 mg, 0.07 mmol, prepared as described inExample 10) was added 1-propanamine (2.0 mL, 20 mmol) and the reactionwas heated to 120° C. for 20 minutes in a CEM Discover microwaveinstrument. The reaction was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 5% methanol inmethylene chloride to give the compound (103, 20.0 mg, 60%). MS (ESI)[M+H⁺]⁺=438.51.

Step 2—Preparation of1-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-propyl-urea(P-0774)

To1-{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methyl]-phenyl}-3-propyl-urea(103, 20.0 mg, 0.04 mmol) in tetrahydrofuran (3 mL) was addedDess-Martin periodane (23.0 mg, 0.055 mmol) under an atmosphere ofnitrogen. The reaction was stirred for 10 minutes. The reaction wasconcentrated and purified by silica gel column chromatography elutingwith 1% methanol in dichloromethane to give the compound (P-0774, 6.0mg, 30%). MS (ESI) [M+H⁺]⁺=436.5.

Additional compounds were prepared following the protocol of Scheme 30,replacing 1-propanamine with an appropriate amine and optionallyreplacing{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid methyl ester P-0065 with an appropriate carbamic acid methyl ester(see Example 10) in Step 1. The following compounds were made followingthis procedure:

-   1-sec-Butyl-3-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1289),-   1-Cyclopentyl-3-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1317),-   1-Butyl-3-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1318),-   1-Butyl-3-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1567),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea    (P-1580),-   1-Butyl-3-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-urea    (P-1586),-   Morpholine-4-carboxylic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1606),-   1-Butyl-3-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-1-methyl-urea    (P-1612),-   1-Butyl-3-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-1-methyl-urea    (P-1884),-   Morpholine-4-carboxylic acid    [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1894),-   1-Butyl-3-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-1-ethyl-urea    (P-1983),-   1-Butyl-3-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-1-ethyl-urea    (P-1994), and-   3-Diethylamino-pyrrolidine-1-carboxylic acid    [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-2015).    The following table indicates the amine (column 2) and the carbamic    acid methyl ester (column 3) used to afford the target compounds    (column 4). Column 1 provides the compound number and column 5 the    observed mass.

MS(ESI) Carbamic acid methyl [M + H⁺]⁺ Amine ester Compound observedP-1289

450.4 P-1317

462.4 P-1318

450.5 P-1567

403.2 P-1580

464.3 P-1586

407.3 P-1606

421.1 P-1612

421.3 P-1884

417.4 P-1894

417.4 P-1983

401.4 P-1994

431.4 P-2015

472.4

The intermediate product of Step 1 of Scheme 30 can alternatively bereacted under reducing conditions to provide analogous compounds inwhich the carbonyl linker of the 3-position of azaindole to the phenylring is methylene. The product of Step 1 is a mixture of the hydroxyland methoxy methyl linker of the 3-position, which may be carriedthrough the reduction Step as the mixture or may be isolated as eitherthe hydroxyl or methoxy for use in this reaction. This reduction isexemplified as follows using the product of Step 1 in the preparation ofP-1567 to prepare1-Butyl-3-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-ureaP-1571.

Step 1—Preparation of1-Butyl-3-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-urea(P-1571)

A mixture of1-Butyl-3-2,4-difluoro-3-[hydroxy-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl-urea(41 mg, 0.000081 mol, isolated from Step 1 of Scheme 30), triethylsilane(2 mL, 0.01 mol), and trifluoroacetic acid (1 mL, 0.01 mol) in 20 ml ofacetonitrile was refluxed for 3 hrs. The mixture was concentrated andthe residue was redissolved in ethyl acetate and sodium bicarbonatesolution. The organic layer was collected and dried over MgSO₄. Anoff-white solid compound was obtained after chromatography (P-1571, 18mg, 57%). MS (ESI) [M−H⁺]⁻=389.2.

Additional compounds were prepared following the protocol of Step 1 ofScheme 30 followed by the reduction step above as Step 2, where theproduct of Scheme 30 Step 1 may be isolated as either the hydroxyl ormethoxy derivative, or used as the mixture, replacing 1-propanamine withan appropriate amine and{2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid methyl ester P-0065 with an appropriate carbamic acid methyl ester(see Example 10) in Step 1. The following compounds were made followingthis procedure:

-   1-Cyclopentyl-3-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-urea    (P-1572),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-3-cyclopentyl-urea    (P-1575),-   1-Butyl-3-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-urea    (P-1587),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea    (P-1594),-   Morpholine-4-carboxylic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-amide    (P-1595),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea    (P-1601),-   1-Cyclopentyl-3-{2,4-difluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenyl}-urea    (P-1615),-   1-Butyl-3-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-1-methyl-urea    (P-1625),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-3-cyclopropylmethyl-urea    (P-1652),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-3-(4-fluoro-phenyl)-urea    (P-1657),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenyl]-3-(4-fluoro-benzyl)-urea    (P-1654), and-   3-Diethylamino-pyrrolidine-1-carboxylic acid    [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amide    (P-2014).    The following table indicates the amine (column 2) and the carbamic    acid methyl ester (column 3) used to afford the target compound    (column 4). For the carbamic acid methyl ester, R can be H or CH₃,    where the compound was either a mixture of the two, or either of the    isolated compounds wherein R is H or R is CH₃. Column 1 provides the    compound number and column 5 the observed mass.

MS(ESI) Carbamic acid methyl [M + H⁺]⁺ Amine ester Compound observedP-1572

401.2 P-1575

405.2 P-1587

393.3 P-1594

450.3 P-1595

407.2 P-1601

419.2 P-1615

525.2 P-1625

407.3 P-1652

391.2 P-1657

461.2 P-1654

445.2 P-2014

458.4

Example 16 Synthesis of 5-Methoxy-1H-pyrrolo[2,3-b]pyridine 104 andRelated Compounds

Compound 104 was synthesized in one step from5-bromo-1H-pyrrolo[2,3-b]pyridine 67 as described in Scheme 31.

Step 1—Preparation of 5-Methoxy-1H-pyrrolo[2,3-b]pyridine (104)

To 5-bromo-7-azaindole (67, 500.0 mg, 2.53 mmol) inN,N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction wasstirred overnight at 120° C. under an atmosphere of Argon. The reactionwas poured into water, and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, filtered. The filtratewas concentrated and purified with silica gel column chromatographeluting with 20% ethyl acetate in hexane to give white solid (104, 140mg, 28%). MS (ESI) [M+H⁺]⁺=149.1. In an alternative method, 2.3 g (11.7mmol) 5-bromo-7-azaindole (67, 2.3 g, 11.7 mmol) was dissolved in 75 mLN,N-dimethylformamide and 50 mL methanol (50 mL), adding sodiummethoxide (32 g, 0.6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) atroom temperature. The reaction was stirred for three hours at 100° C.under an atmosphere of argon. The mixture was diluted with ethyl acetateand poured into a solution of ammonium chloride:ammonium hydroxide(4:1). The organic layer was extracted with ammonium chloride:ammoniumhydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated. The desired compound was isolated by silicagel column chromatography eluting with 30% to 70% ethyl acetate inhexanes to give a yellow solid (104, 0.27 g, 15.6%). MS (ESI)[M+H⁺]⁺=149.2.

5-Ethoxy-1H-pyrrolo[2,3-b]pyridine 506

was prepared using the protocol of Scheme 31, substituting methanol withethanol and sodium methoxide with sodium ethoxide.

5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine 507

was prepared using the protocol of Scheme 31, substituting methanol with2-Methoxy-ethanol and sodium methoxide with sodium 2-Methoxy-ethoxide(prepared from 2-Methoxy-ethanol and sodium hydride). MS (ESI)[M+H⁺]⁺=193.3.

Diethyl-[2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-ethyl]-amine 508

was prepared using the protocol of Scheme 31, substituting methanol with2-diethylamino-ethanol and sodium methoxide with sodium2-diethylamino-ethoxide (prepared from 2 2-diethylamino-ethanol andsodium hydride). MS (ESI) [M+H⁺]⁺=234.5.

Example 17 Synthesis of 5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89

5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 was synthesized in one stepfrom 5-bromo-1H-pyrrolo[2,3-b]pyridine 67 as described in Scheme 32.

Step 1—Preparation of 5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89)

To 5-bromo-7-azaindole (67, 1.00 g, 5.08 mmol) in water (13.0 mL) andacetonitrile (36 mL) were added pyridine-3-boronic acid (609, 1.0 g, 8.1mmol), potassium carbonate (1.79 g, 0.0130 mol) andTetrakis(triphenylphosphine)palladium(0) (50.0 mg, 0.043 mmol) under anatmosphere of nitrogen. The reaction mixture was heated to 170° C.overnight. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and concentrated. The residue was purified with silicagel column chromatography eluting with 25% ethyl acetate in hexane toprovide a light yellow solid (89, 820 mg, 82%). MS (ESI) [M+H⁺]⁺=196.1.

Additional compounds were prepared following the protocol of Scheme 32,either by substituting pyridine-3-boronic acid with an appropriateboronic acid or by substituting the 5-bromo-7-azaindole with5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineand reacting with a suitable aryl or heteroaryl halide (i.e. couplingwith the boronic acid ester on the azaindole, and the halide on thegroup to be coupled to the 5-position of the azaindole). The followingcompounds were prepared by this procedure:

-   5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine (514),-   5-(4-Fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine (605),-   5-Phenyl-1H-pyrrolo[2,3-b]pyridine,-   5-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine,-   5-(2-Methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine,-   5-Pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine,-   4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-benzenesulfonamide,-   3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-benzenesulfonamide,-   5-Pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine,-   5-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine (P-0173), and-   3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-benzamide (P-1622).    The following table indicates either 5-bromo-7-azaindole or    5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine    starting material (column 1) and the appropriate reagent to be    coupled to the 5 position of the azaindole (column 2) to afford the    resulting compound (column 3), with the observed mass given in    column 4.

MS(ESI) Reagent coupled to [M + H⁺]⁺ Starting azaindole 5 positionCompound observed

229.1

213.1

195.2

226.2

227.2

196.2

274.1

274.1

197.2

273.1

238.2

Example 18 Synthesis of3-(4-(4-chlorobenzyloxy)-3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridineP-1247

Compound P-1247 was synthesized in three steps from4-hydroxy-3-methoxybenzaldehyde 105 as shown in Scheme 33.

Step 1—Preparation of 4-(4-chlorobenzyloxy)-3-methoxybenzaldehyde (106)

To 4-hydroxy-3-methoxybenzaldehyde (105, 600.0 mg, 3.94 mmol) and4-chlorobenzyl bromide (557, 1.20 g, 5.84 mmol) in acetonitrile (6 mL)was added potassium carbonate (0.390 g, 2.82 mmol). The reaction wasmicrowaved on 300 watts, 120° C. for 10 minutes. The reaction wasextracted with ethyl acetate and water. The organic layer was washedwith brine, dried over magnesium sulfate, filtered and the volatilesremoved by evaporation. The desired compound was purified byrecrystallization from hexanes to provide 106 (1.01 g, 93%). MS (ESI)[M−H⁺]⁻275.1.

Step 2—Preparation of3-((4-(4-chlorobenzyloxy)-3-methoxyphenyl(methoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(107)

To 1H-Pyrrolo[2,3-b]pyridine (94, 0.235 g, 1.99 mmol) and4-(4-chlorobenzyloxy)-3-methoxybenzaldehyde (106, 0.500 g, 1.81 mmol)was added 5 mL of methanol followed by the addition of solid potassiumhydroxide (0.203 g, 3.61 mmol). The reaction was allowed to stir atambient temperature for 18 days. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was separatedand volatiles removed to give a solid which was suspended in hot ethylacetate. The suspension was allowed to cool and the solid collected byvacuum filtration to provide 107 (548 mg, 74%). MS (ESI) [M+H⁺]⁺=409.4.

Step 3—Preparation of3-(4-(4-chlorobenzyloxy)-3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine(P-1247)

To3-((4-(4-chlorobenzyloxy)-3-methoxyphenyl)(methoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(107, 0.548 g, 1.34 mmol) in acetonitrile (20 mL) was addedtrifluoroacetic acid (1.7 mL, 2.21 mmol) and triethylsilane (3.47 mL,2.17 mmol). The reaction was stirred at 60° C. for 15 hours. Thevolatiles were removed and the desired compound was purified by silicagel chromatography, eluting with a gradient from 0% to 60% ethyl acetatein hexanes to provide a white solid (P-1247, 505 mg, 99%). MS (ESI)[M+H⁺]⁺=379.4.

Additional compounds were prepared using the protocol of Scheme 33,Steps 2 and 3, replacing 4-(4-chlorobenzyloxy)-3-methoxybenzaldehyde 106with a suitable aldehyde (prepared as described in Example 34), andoptionally replacing 1H-Pyrrolo[2,3-b]pyridine 94 with an appropriatesubstituted 7-azaindole (see Example 9 or Example 16) in Step 2. Thefollowing compounds were made following this procedure:

-   3-[3-Methoxy-4-(4-trifluoromethyl-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1721),-   3-[3-Trifluoromethyl-4-(4-trifluoromethyl-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1797),-   3-{3-Methoxy-4-[4-(4-methyl-piperazin-1-ylmethyl)-benzyloxy]-benzyl}-1H-pyrrolo[2,3-b]pyridine    (P-1821),-   3-[4-(4-Chloro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1844),-   3-[4-(3-Fluoro-4-trifluoromethyl-benzyloxy)-3-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1849),-   3-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-3-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1851),-   2-[2-Methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole    (P-1870),-   3-[4-(4-Chloro-2-fluoro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine    (P-1885),-   3-[4-(3,4-Dichloro-benzyloxy)-3-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1886),-   3-[4-(4-Chloro-benzyloxy)-3-fluoro-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1896),-   2-[2-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole    (P-1899),-   3-(4-Benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine    (P-1901),-   5-Chloro-3-[4-(4-chloro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1970),-   5-Chloro-3-[4-(4-chloro-2-fluoro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1972),-   3-[4-(4-Chloro-2-fluoro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1973),-   2-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxymethyl]-1H-benzoimidazole    (P-1976),-   2-[5-Fluoro-2-methoxy-4-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole    (P-1977),-   2-[5-Fluoro-2-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazole    (P-1978),-   3-{4-[2-(2-Bromo-ethoxy)-ethoxy]-2-fluoro-5-methoxy-benzyl}-5-chloro-1H-pyrrolo[2,3-b]pyridine    (P-1984),-   5-Chloro-3-[2,5-difluoro-4-(2-methoxy-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1986),-   5-Chloro-3-[2-fluoro-5-methoxy-4-(2-methoxy-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1990),-   {3-[4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-5-fluoro-2-methoxy-phenoxy]-propyl}-diethyl-amine    (P-2004),-   5-Chloro-3-{2-fluoro-5-methoxy-4-[2-(2-methoxy-ethoxy]-ethoxy-benzyl}-1H-pyrrolo[2′,3-b]pyridine    (P-20012),-   3-(4-Benzyloxy-2,6-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine    (P-2022),-   3-{2-Fluoro-5-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl}-5-methoxy-1H-pyrrolo[2,3-b]pyridine    (P-2025), and-   3-{2-Fluoro-5-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-benzyl}-1H-pyrrolo[2,3-b]pyridine    (P-2026).    The following table indicates the aldehyde (column 2) and the    azaindole (column 3) used to afford the target compound (column 4).    Column 1 indicates the compound number and column 5 the observed    mass.

MS(ESI) [M + H⁺]⁺ Aldehyde Azaindole Compound observed P-1721

413.2 P-1797

451.3 P-1821

457.4 P-1844

397.2 P-1849

432.4 P-1851

P-1870

385.4 P-1885

445.3 P-1886

413.3 P-1896

367.3 P-1899

373.4 P-1901

351.4 P-1970

431.2 P-1972

449.2 P-1973

415.3 P-1976

437.3 P-1977

433.4 P-1978

403.4 P-1984

457.4 459.4 P-1986

353.4 P-1990

365.3 P-2004

420.4 P-2002

409.3 P-2022

438.1 P-2025

405.2 P-2026

373.2

Example 19 Synthesis of Propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amideP-0955 and Related Compounds

As an alternative method to that of Example 2, compound P-0955 wassynthesized in nine steps from 4-chloro-2-fluoro-phenylamine 47 as shownin Scheme 37.

Step 1 Preparation of 3-Amino-6-chloro-2-fluoro-benzoic acid benzylester (48)

To 4-chloro-2-fluoro-phenylamine (47, 6.30 mL, 57.0 mmol) intetrahydrofuran (300 mL), cooled with dry ice/acetone bath under anatmosphere of nitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) wasadded slowly. After 20 minutes, 1,2-Bis-(chloro-dimethyl-silanyl)-ethane(12.9 g, 60.0 mmol) dissolved in tetrahydrofuran (40.0 mL) was addedslowly to the reaction. After 1 hour, n-butyllithium (2.50 M in hexane,25.0 mL) was added slowly to the reaction. The reaction was stirred at−78° C. for 20 minutes and then allowed to warm to room temperature over60 minutes. The reaction was cooled to −78° C., followed by addition ofn-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes,benzyl chloroformate (10.0 mL, 70.0 mmol) was added to the reaction. Thereaction mixture was stirred at −78° C. overnight followed by additionof water (80 mL) and concentrated hydrochloric acid (25 mL). Thereaction was allowed to warm to room temperature for 2 hours. Theorganic layer was separated. The aqueous layer was basified withpotassium carbonate and extracted with ethyl acetate. The organic layerswere combined and washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The desired compound was isolated bysilica gel column chromatography (ethyl acetate/hexane 20%) to give acolorless oil (48, 12.5 g, 78.3%). MS (ESI) [M+H⁺]⁺=280.0.

Step 2—Preparation of6-chloro-2-fluoro-3-(propane-1-sulfonylamino-benzoic acid benzyl ester(49)

To 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (48, 1.20 g, 4.3mmol) in methylene chloride (28 mL) was added pyridine (0.52 mL, 6.4mmol) and propanesulfonyl chloride (0.685 g, 4.8 mmol). The reaction wasstirred at room temperature overnight, then poured into water, andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thedesired compound was isolated with silica gel column chromatography togive a colorless oil (49, 960 mg, 58.0%). MS (ESI) [M−H⁺]⁺=384.1.

Step 3—Preparation of6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (115)

To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzylester (49, 6.00 g, 15.6 mmol) in tetrahydrofuran (100 mL) was added 1.0M aqueous potassium hydroxide (100 mL). The reaction was heated toreflux overnight. The reaction was poured into water, acidified to pH 2with 1 N hydrochloric acid and extracted with ethyl acetate. The organicportion was dried over anhydrous sodium sulfate, filtered andconcentrated to give a white solid 115 (3.95 g, 85.8%).

Step 4—Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid(50)

To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (115, 0.69g, 2.3 mmol) in methanol (10 mL) was added 20% palladium hydroxide oncarbon (200 mg). The reaction was stirred under hydrogen at 50 psi for 2hours. The reaction was filtered and concentrated to give white solid 50that was used in the next step. MS (ESI) [M−H⁺]⁻=260.1.

Step 5—Preparation of 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acidmethyl ester (501)

To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (50, 5.05 g,0.0193 mol) in methylene chloride (100 mL) was addedN,N-dimethylformamide (0.075 mL, 0.97 mmol) under an atmosphere ofnitrogen. The reaction was cooled with ice/water, followed by slowaddition of Oxalyl chloride (2.00 M of in methylene chloride, 10.8 mL,21.6 mmol). The reaction mixture was stirred at room temperature for 3.0hours. The reaction was cooled with ice/water, followed by addition ofmethanol (36.0 mL, 0.89 mol) slowly. The reaction was stirred at roomtemperature overnight. The reaction was concentrate and purified withsilica gel column chromatography eluting with 30% ethyl acetate inhexane to give a crude white solid 4.0 g.

Step 6—Preparation of Propane-1-sulfonic acid(2-fluoro-3-hydroxymethyl-phenyl)-amide (502)

To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl ester (501,3.80 g, 13.8 mmol) in tetrahydrofuran (133 mL) was added lithiumtetrahydroaluminate (1.00 M in tetrahydrofuran, 20.0 mL, 20.0 mmol)under an atmosphere of nitrogen at room temperature. The reaction wasstirred at room temperature for 8 hours, followed by addition of 10 g ofNaSO₄.10H₂O. After 12 hours, the reaction was filtered, concentrated andpurified with silica gel column chromatography eluting with 5% methanolin methylene chloride to give a white solid (502, 3.0 g, 87.9%).

Step 7—Preparation of propane-1-sulfonic acid(2-fluoro-3-formyl-phenyl)-amide (503)

To propane-1-sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (502,0.20 g, 0.81 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martinperiodinane (0.377 g, 0.89 mmol). The reaction was stirred at roomtemperature for 10 minutes, then poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 20% ethyl acetate inhexane to give a white solid (503, 100 mg, 50.0%). MS (ESI)[M−H⁺]⁺=244.1.

Step 8—Preparation of Propane-1-sulfonic acid{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2-fluoro-phenyl}-amide(504)

To 5-bromo-7-azaindole 67 (312 mg, 1.58 mmol) in methanol (28 mL) wereadded propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (503, 370mg, 1.5 mmol) and potassium hydroxide (422.8 mg, 7.5 mmol) under anatmosphere of nitrogen. The reaction was stirred at room temperatureovernight, then poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% ethyl acetate in hexane to give thedesired compound as white solid (504, 300 mg, 45.0%).

Step 9—Preparation of propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide(P-0955)

To Propane-1-sulfonic acid{3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2-fluoro-phenyl}-amide(504, 0.650 g, 1.47 mmol) in tetrahydrofuran (25.0 mL) cooled withice/water was added Dess-Martin periodinane (0.748 g, 1.76 mmol). Thereaction was stirred at room temperature for 15 minutes. The reactionwas poured into water containing sodium thiosulfate and potassiumcarbonate and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% ethyl acetate in hexane and washed with ethyl acetate to givewhite solid. (P-0955, 0.35 g, 54.1%). MS (ESI) [M+H⁺]⁺=460.0, 462.0.

Butane-1-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amideP-1250

was prepared following the protocol of Scheme 37, substitutingpropane-2-sulfonyl chloride with butane-1-sulfonyl chloride in Step 1and 5-bromo-1H-pyrrolo[2,3-b]pyridine 67 with5-chloro-1H-pyrrolo[2,3-b]pyridine 80 (see Example 9) in step 8.

MS (ESI) [M−H⁺]⁻=408.1.

Propane-1-sulfonic acid[2-fluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amideP-1256

was prepared following the protocol of Scheme 37, substituting5-bromo-1H-pyrrolo[2,3-b]pyridine 67 with5-methoxy-1H-pyrrolo[2,3-b]pyridine 104 (see Example 16) in step 8. MS(ESI) [M−H⁺]⁻=390.1.

N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]benzenesulfonamideP-1255

was prepared following the protocol of Scheme 37, substitutingpropane-2-sulfonyl chloride with benzenesulfonyl chloride in Step 1 and5-bromo-1H-pyrrolo[2,3-b]pyridine 67 with5-chloro-1H-pyrrolo[2,3-b]pyridine 80 (see Example 9) in step 8. MS(ESI) [M−H⁺]⁺=428.0.

Example 20 Synthesis of3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-propionicacid P-1270

Compound P-1270 was synthesized in three steps from propane-1-sulfonicacid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amideP-0773 as shown in Scheme 38.

Step 1—Preparation of(E)-3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-acrylicacid methyl ester (505)

To propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide(P-0773, 125.0 mg, 0.27 mmol, prepared as described in Example 4) inN,N-dimethylformamide (4.0 mL) were added palladium acetate (15 mg,0.068 mmol), triphenylphosphine (36 mg, 0.14 mmol), methyl acrylate(0.098 mL, 1.1 mmol) and triethylamine (0.114 mL, 0.82 mmol) under anatmosphere of nitrogen. The reaction was stirred at 140° C. overnight,then poured into water, acidified with water and extracted with ethylacetate. To the filtrate in methylene chloride (5.0 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL, 3.3 mmol). The reaction wasstirred at room temperature for 3 hours. The reaction was concentratedand purified with silica gel column chromatography eluting with 30%ethyl acetate in hexane to give a light yellow oil that was useddirectly in the next step.

Step 2—Preparation of3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-acrylicacid (P-1269)

To(E)-3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-acrylicacid methyl ester (100.0 mg, 0.22 mmol) in tetrahydrofuran (5.0 mL) andwater (1.50 mL) was added lithium hydroxide (21 mg, 0.86 mmol). Thereaction was stirred at room temperature overnight. The reaction waspoured into water, acidified with 1N HCl to pH around 1, and thenextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 20% ethyl acetate inhexane to give a white solid (P-1269, 30 mg). MS (ESI) [M−H⁺]⁻=448.0.

Step3—3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-propionicacid (P-1270)

To3-3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-acrylicacid (P-1269, 20.0 mg, 0.045 mmol) in methanol (5.0 mL) was added 20%Pd(OH)₂/C (10 mg) under an atmosphere of hydrogen. The reaction wasstirred at room temperature for 2 hours. The reaction mixture wasfiltered, concentrated and purified with silica gel columnchromatography eluting with 10% methanol in methylene chloride to give awhite solid (P-1270, 8.8 mg). MS (ESI) [M−H⁺]⁻=450.1.

Example 21 Synthesis of thiophene-2-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide 508

Compound 512 was synthesized in four steps from 2,4-difluorophenylamine42 as shown in Scheme 39.

Step 1—Preparation of 3-amino-4,2-difluoro-benzoic acid ethyl ester(509)

To 4,2-difluoro-phenylamine (42, 6.30 mL, 57.0 mmol) in tetrahydrofuran(300 mL), cooled with dry ice/acetone bath under an atmosphere ofnitrogen, n-butyllithium (2.50 M in hexane, 24.4 mL) was added slowly.After 20 minutes, 1,2-Bis-(chloro-dimethyl-silanyl)-ethane (12.9 g, 60.0mmol) dissolved in tetrahydrofuran (40.0 mL) was slowly added to thereaction. After 1 hour, n-butyllithium (2.50 M in hexane, 25.0 mL) wasslowly added to the reaction. The reaction was stirred at −78° C. for 20minutes and then allowed to warm to room temperature over 60 minutes.The reaction was cooled to −78° C., followed by addition ofn-butyllithium (2.50 M in hexane, 26.0 mL) slowly. After 80 minutes,ethyl chloroformate (6.69 mL, 70.0 mmol) was added to the reaction. Thereaction mixture was stirred at −78° C. overnight followed by additionof water (80 mL) and concentrated hydrochloric acid (25 mL). Thereaction was allowed to warm to room temperature for 2 hours. Theorganic layer was separated. The aqueous layer was basified withpotassium carbonate and extracted with ethyl acetate. The organic layerswere combined and washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The desired compound was isolated bysilica gel column chromatography (ethyl acetate/hexane 20%) to give acolorless oil (509, 4.6 g, 39%). MS (ESI) [M+H⁺]⁺=218.1.

Step 2—Preparation of 2,6-difluoro-3-(thiophene-2-sulfonylamino)-benzoicacid ethyl ester (510)

To 3-amino-2,4-difluoro-benzoic acid ethyl ester (509, 1.20 g, 5.93mmol) in methylene chloride (28 mL) was added pyridine (0.52 mL, 6.4mmol) and thiophene-2-sulfonyl chloride (0.97 g, 5.38 mmol). Thereaction was stirred at room temperature overnight, then poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The desired compound was isolated with silica gel columnchromatography (ethyl acetate/hexane 20%) to give a colorless oil (510,1.2 g, 65.0%). MS (ESI) [M +H⁺]⁺=348.2.

Step 3—Preparation of thiophene-2-sulfonic acid(2,4-difluoro-3-hydroxyethyl-phenyl)-amide (511)

To 2,6-difluoro-3-(thiophene-2-sulfonylamino)-benzoic acid ethyl ester(510, 1.6 g, 3.5 mmol) in tetrahydrofuran (25.0 mL) was added lithiumtetrahydroaluminate (1.00 M in tetrahydrofuran, 8.08 mL, 8.08 mmol)under an atmosphere of nitrogen at room temperature. The reaction wasstirred at room temperature for 8 hours, followed by addition of 10 g ofNaSO₄.10H₂O. After 12 hours, the reaction was filtered, concentrated andpurified with silica gel column chromatography eluting with 5% methanolin methylene chloride to give a white solid (511, 300.0 mg, 21.0%).

Step 4—Preparation of thiophene-2-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (512)

To thiophene-2-sulfonic acid (2,4-difluoro-3-hydroxymethyl-phenyl)-amide(511, 0.46 g, 1.52 mmol) in tetrahydrofuran (5.0 mL) was addedDess-Martin periodinane (0.71 g, 1.67 mmol). The reaction was stirred atroom temperature for 10 minutes, then poured into water and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 20% ethyl acetate inhexane to give a white solid (512, 100 mg, 21%). MS (ESI) [M+H⁺]⁺=304.2.

Thiophene-3-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 513

was prepared following the protocol of Scheme 39, substitutingthiophene-2-sulfonyl chloride with thiophene-3-sulfonyl chloride in Step2. MS (ESI) [M+H⁺]⁺=304.2.

N-(2,4-Difluoro-3-formyl-phenyl)-methanesulfonamide 577

was prepared following the protocol of Scheme 39, substitutingthiophene-2-sulfonyl chloride with methanesulfonyl chloride in Step 2.

N-(2,4-Difluoro-3-formyl-phenyl)-3-fluoro-benzenesulfonamide 578

was prepared following the protocol of Scheme 39, substitutingthiophene-2-sulfonyl chloride with 3-fluoro-benzenesulfonyl chloride inStep 2.

Example 22 Synthesis of4-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylicacid butylamide P-1486 and related compounds

Compound P-1486 was synthesized in three steps from1H-indole-4-carbaldehyde 518 as shown in Scheme 41.

Step 1—Preparation of 4-Formyl-indole-1-carboxylic acid butylamide (519)

To 1H-Indole-4-carbaldehyde (518, 1.57 g, 10.8 mmol) in acetonitrile (20mL) was added 1-isocyanatobutane (1.81 mL, 16.2 mmol), followed by4-dimethylaminopyridine (130 mg, 1.1 mmol). The reaction was refluxedfor 48 hours. The reaction solution was quenched with 1 M HCl (aq.) andextracted with ethyl acetate. The organic layer was washed with sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate, filtratedand concentrated to give a light yellow solid (519, 2.62 g, 45%). MS(ESI) [M+H⁺]⁺245.2.

Step 2—Preparation of4-[Hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-indole-1-carboxylicacid butryamide (520)

To 5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 51 mg, 0.26 mmol,prepared as in Example 17) in methanol (2 mL), was added4-Formyl-indole-1-carboxylic acid butylamide (519, 84 mg, 0.34 mmol) andpotassium hydroxide (44 mg, 0.78 mmol). The reaction was stirred at roomtemperature overnight. The reaction was poured into water and extractedwith ethyl acetate. The organic layer was washed with water and brine,dried over anhydrous magnesium sulfate, filtrated and concentrated. Thedesired compound was isolated with silica gel column chromatography togive an off-white solid (520, 7 mg, 6%). MS (ESI) [M+H⁺]⁺=440.3.

Step 3—Preparation of4-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylicacid butylamide (P-1486)

-   To    4-[Hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-indole-1-carboxylic    acid butylamide (520, 7 mg, 0.016 mmol) in tetrahydrofuran (1 mL)    was added Dess-Martin periodinane (7.4 mg, 0.017 mmol). The reaction    was stirred at room temperature for 30 minutes, then poured into    water and extracted with ethyl acetate. The organic layer was washed    with saturated sodium bicarbonate and brine, dried over anhydrous    magnesium sulfate, filtrated and concentrated. The desired compound    was purified by Prep HPLC using a gradient of buffer A (5%    acetonitrile, 95% water, 0.1% formic acid) and buffer B (95%    acetonitrile, 5% water, 0.1% formic acid). P-1486 was isolated as a    fluffy white solid (2.8 mg, 40%). MS (ESI) [M+H⁺]⁺=438.3.

Additional compounds were prepared following the protocol of Scheme 41,optionally substituting 1-isocyanatobutane with an appropriateisocyanate in Step 1 under suitable base/solvent conditions(dimethylaminopyridine and acetonitrile per Scheme 41 Step 1 orappropriate conditions) and optionally substituting5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with a suitable 7-azaindolein Step 2. The azaindole was purchased or synthesized as described inExamples 16 and 17. The following compounds were made following thisprocedure:

-   (1-Benzyloxymethyl-1H-indol-4-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1523),-   (1-Benzenesulfonyl-1H-indol-4-yl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1524),-   4-(5-Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylic    acid butylamide (P-1576),-   4-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylic    acid butylamide (P-1602),-   4-(5-Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylic    acid benzylamide (P-1611),-   4-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylic    acid benzylamide (P-1618),-   4-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylic    acid butylamide (P-1687),-   4-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-sulfonic    acid dimethylamide (P-1744),-   (1-But-2-ynyl-1H-indol-4-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1820),-   4-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-sulfonic    acid butyl-methyl-amide (P-1830),-   4-[5-(4-Sulfamoyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylic    acid butylamide (P-1854),-   4-[5-(3-Sulfamoyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylic    acid butylamide (P-1858),-   4-[5-(2-Methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylic    acid butylamide (P-1860),-   4-(5-Pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylic    acid butylamide (P-1862),-   4-(5-Methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylic    acid butylamide (P-1875), and-   4-[5-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylic    acid (pyridin-3-ylmethyl)-amide (P-1887).    The following table indicates the base/solvent (column 2) and    isocyanate used in Step 1 (column 3), and the 7-azaindole used in    Step 2 (column 4) to afford the target compound (column 5). Column 1    provides the compound number and column 6 the observed mass.

Step 1 MS(ESI) Base/ Step 1 [M + H⁺]⁺ Solvent reagent Azaindole Compoundobserved P-1523 NaH/ THF

459.4 P-1524 KOH/ CH₂Cl₂ water

480.1 482.1 P-1576 *

437.3 P-1602 *

471.2 P-1611 *

471.3 P-1618 *

505.2 P-1687 *

439.2 441.2 P-1744 NaH/ THF

446.2 P-1820 NaH/ THF

391.2 P-1830 KOH/ CH₂Cl₂ water

P-1854 *

514.2 [M − H⁺]⁺ P-1858 *

516.2 P-1860 *

469.3 P-1862 *

439.3 P-1875 *

391.4 P-1887 *

503.4 * per Scheme 41 (i.e. dimethylaminopyridine and acetonitrile)

The product of Step 2 of Scheme 41 can alternatively be reacted to formthe corresponding compounds with methylene linker at the 3 position ofthe azaindole. For example,4-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylicacid butylamide P-1656 was prepared from4-[Hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-indole-1-carboxylicacid butylamide 520 as shown in Scheme 41a.

Step 1—Preparation of4-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylicacid butylamide (P-1656)

A mixture of4-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-indole-1-carboxylicacid butylamide (520, 18 mg, 0.041 mmol), trifluoroacetic acid (0.5 mL),triethylsilane (1 mL), and acetonitrile (8 mL) was refluxed for 4 hours.The reaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with saturated sodium bicarbonate and brine,dried over anhydrous magnesium sulfate, filtrated and concentrated. Thedesired compound was purified by Prep HPLC using a gradient of buffer A(5% acetonitrile, 95% water, 0.1% formic acid) and buffer B (95%acetonitrile, 5% water, 0.1% formic acid). P-1656 was isolated as anoff-white solid (4.8 mg, 28%). MS (ESI) [M+H⁺]⁺=424.2.

The corresponding hydroxy-methyl derivative of Scheme 41 Step 2 wasreacted following the protocol of Scheme 41a to prepare4-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-indole-1-carboxylicacid butylamide P-1861,4-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylicacid butylamide P-1876, and4-(5-Pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylicacid butylamide P-1877, with structures shown below.

Example 23 Synthesis of(3-Benzyloxy-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1467 and related compounds

Compound P-1467 was synthesized in four steps from 2,4-difluorophenol 35as shown in Scheme 43.

Step 1—Preparation of 1-Benzyloxy-2,4-difluoro-benzene (525)

To 2,4-difluoro-phenol (35, 7.60 g, 0.0584 mol) in N,N-dimethylformamide(50.0 mL) were added benzyl bromide (8.0 mL, 0.067 mol) and potassiumcarbonate (9.00 g, 0.0651 mol) under an atmosphere of nitrogen. Thereaction was stirred at room temperature overnight. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% ethyl acetate in hexane to give the compound as white solid(525, 3.20 g, 25%).

Step 2—Preparation of 3-Benzyloxy-2,6-difluoro-benzaldehyde (526)

To 1-Benzyloxy-2,4-difluoro-benzene (525, 3.00 g, 13.6 mmol) inTetrahydrofuran (48 mL) under an atmosphere of nitrogen and cooled withdry ice/acetone was added n-Butyllithium (1.60 M in hexane, 8.94 mL).After 20 minutes, N,N-dimethylformamide (1.46 mL, 0.0189 mol) was addedto the reaction. After another 20 minutes, the flask was stirred at roomtemperature for 30 minutes. The reaction mixture was poured into water,acidified to pH=1, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, concentrated andpurified with silica gel column chromatography eluting with 30% ethylacetate in hexane to give the compound as a yellow solid (526, 2.5 g,74%).

Step 3—Preparation of(3-Benzyloxy-2,6-difluoro-phenyl)-(5pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(527)

To 5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 750.0 mg, 0.003842 mol,prepared as in Example 17) in methanol (20.0 mL) were added3-Benzyloxy-2,6-difluoro-benzaldehyde (526, 1.12 g, 4.5 mmol) andpotassium hydroxide (1.50 g, 0.0267 mol) under an atmosphere ofnitrogen. The reaction was stirred at room temperature overnight andthen poured into water, acidified with 1N HCl to pH around 2 andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 20% ethyl acetate inhexane to give the compound (527, 700 mg, 35%).

Step 4—Preparation of(3-Benzyloxy-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1467)

To(3-Benzyloxy-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(527, 300.0 mg, 0.68 mmol) in tetrahydrofuran (10.0 mL) was addedDess-Martin periodinane (344 mg, 0.81 mmol). The reaction was stirred atroom temperature for 10 minutes. The reaction mixture was concentratedwith silica and purified with silica gel column chromatography elutingwith 10% methanol in dichloromethane to give the compound (P-1467, 240mg, 80%). MS (ESI) [M+H⁺]⁺=442.2.

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2,6-difluoro-3-(2-methoxy-ethoxy)-phenyl]-methanoneP-1453

was prepared following the protocol of Scheme 43, substituting benzylbromide with 1-Bromo-2-methoxy-ethane in Step 1 and5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with5-Bromo-1H-pyrrolo[2,3-b]pyridine (67) in Step 3. MS (ESI)[M+H⁺]⁺=410.1, 412.1.

[2,6-Difluoro-3-(2-methoxy-ethoxy)-phenyl]-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1584

was prepared following the protocol of Scheme 43, substituting benzylbromide with 1-Bromo-2-methoxy-ethane in Step 1 and5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with5-methoxy-1H-pyrrolo[2,3-b]pyridine (104, prepared as in Example 22) inStep 3. MS (ESI) [M+H⁺]⁺=363.2.

(3-Benzyloxy-2,6-difluoro-phenyl)-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1597

was prepared following the protocol of Scheme 43, substituting5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with5-methoxy-1H-pyrrolo[2,3-b]pyridine (104, prepared as in Example 16) inStep 3. MS (ESI) [M+H⁺]⁺=395.2.

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-difluoro-3-methoxy-phenyl)-methanoneP-1386

was prepared following the protocol of Steps 2, 3 and 4 of Scheme 43,substituting 1-Benzyloxy-2,4-difluoro-benzene 525 with2,4-Difluoro-1-methoxy-benzene in Step 2 and5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with5-bromo-1H-pyrrolo[2,3-b]pyridine (67) in Step 3. MS (ESI) [M+H⁺]=367.0,369.0.

(3-Benzyloxy-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1802

was prepared following the protocol of Scheme 43, substituting5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with 7-azaindole. To a solutionof(3-benzyloxy-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-h]pyridin-3-yl)-methanone(P-1802, 0.5 g, 1.37 mol) in methanol (70 mL) and tetrahydrofuran (30mL) was added palladium on carbon (120 mg, 10% wt., 0.58 mol). Themixture was stirred under hydrogenation (60 psi) for six hours. Afterremoval of solvent, the residue was dried under vacuum, which provided(2,6-Difluoro-3-hydroxy-phenyl)-(1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone651

as a white solid (363 mg, 96%). MS (ESI) [M+H⁺]⁺=275.36.

Additional compounds were prepared following steps 3 and 4 of Scheme 43,replacing 3-benzyloxy-2,6-difluoro-benzaldehyde 526 with an appropriatealdehyde and/or pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with anappropriate azaindole in Step 3. The azaindoles used were synthesized asdescribed in Examples 9 or 16. The aldehydes used were synthesized asdescribed in Example 5 or 21. The following compounds were madefollowing this procedure:

-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3,5-dimethoxy-phenyl)-methanone    (P-1463),-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-fluoro-5-trifluoromethyl-phenyl)-methanone,-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-trifluoromethoxy-phenyl)-methanone,-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-trifluoromethyl-phenyl)-methanone,-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3,5-dichloro-phenyl)-methanone,-   (2,6-Dichloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,-   (2,6-Difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,-   (2,6-Dimethyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,-   (2,6-Dichloro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,-   (2,6-Difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,-   (2,6-Dimethyl-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-methanone    (P-1513),-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-difluoromethoxy-phenyl)-methanone    (P-1514),-   (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanone    (P-1551),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-1541),-   N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-1542),-   N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide    (P-1581),-   N-[2,4-Difluoro-3-(5-methoxy-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide    (P-1582),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide    (P-1583),-   N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide    (P-1598),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-trifluoromethyl-benzenesulfonamide    (P-1599),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-{2-fluoro-5-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl}-methanone    (P-2003),-   (4-Benzyloxy-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2020), and-   [4-(4-Chloro-benzyloxy)-3-methoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1698).    The following table indicates the aldehyde (column 2) and the    azaindole (column 3) used to afford the target compound (column 4).    Column 1 provides the compound number and column 5 the observed    mass.

MS(ESI) [M + H⁺]⁺ Aldehyde Azaindole Compound observed P- 1463

361.1 363.0 567

568

569

570

571

572

573

574

575

576

P- 1513

381.0 383.0 P- 1514

367.1 369.1 P- 1551

381.1 383.1 P- 1541

516.2 P- 1542

512.2 P- 1581

462.2 P- 1582

462.2 P- 1583

466.1 P- 1598

510.1 P- 1599

514.0 P- 2003

423.3 P- 2020

363.1 P- 1698

393.2

Example 24 Synthesis of3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridineP-1455

Compound P-1455 was synthesized in four steps from 2,4-difluorophenol 35as shown in Scheme 43a.

Steps 1-3 are identical to Steps 1-3 of Scheme 43.

Step 4—Preparation of3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine(P-1455)

To(3-Benzyloxy-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(527, 580.0 mg, 1.3 mmol) in acetonitrile (29.0 mL) were addedtrifluoroacetic acid (1.9 mL, 0.025 mol) and triethylsilane (3.9 mL,0.024 mol). The reaction was stirred at 80° C. for 1 hour. The reactionwas poured into water, basified with 1 M potassium carbonate to pH=4,and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 50% ethylacetate in hexane to give as a yellow solid (P-1455, 530 mg). MS (ESI)[M+H⁺]⁺=428.3.

Bromo-3-[2,6-difluoro-3-(2-methoxy-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridineP-1454

was prepared following the protocol of Scheme 43a by substituting benzylbromide with 1-Bromo-2-methoxy-ethane in Step 1 and5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine with5-Bromo-1H-pyrrolo[2,3-b]pyridine (67) in Step 3. MS (ESI)[M+H⁺]⁺=410.1, 412.1.

Additional compounds were prepared following steps 3 and 4 of Scheme43a, replacing 3-benzyloxy-2,6-difluoro-benzaldehyde 526 with anappropriate aldehyde and/or pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89with an appropriate azaindole (see Example 9 or Example 16) in Step 3.The following compounds were made following this procedure:

-   5-Bromo-3-(3,5-dimethoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1464),-   3-(3,5-Bis-difluoromethoxy-benzyl)-5-bromo-1H-pyrrolo[2,3-b]pyridine    (P-1538),-   3-(2,6-Dichloro-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1483).-   3-(2,6-Difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1482),-   3-(2,6-Dimethyl-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-0333),-   3-(2,6-Dichloro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine    (P-1478),-   3-(2,6-Difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine    (P-1477),-   3-(2,6-Dimethyl-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine    (P-1481),-   N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide    (P-1590),-   N-[2,4-Difluoro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide    (P-1600),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-methanesulfonamide    (P-1603), and-   N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-methanesulfonamide    (P-1605).    The following table indicates the aldehyde (column 2) and the    azaindole (column 3) used to afford the target compound (column 4).    Column 1 indicates the compound number and column 5 the observed    mass.

MS(ESI) [M + H⁺]⁺ Aldehyde Azaindole Product observed P-1464

347.1 349.1 P-1538

419.1 421.1 P-1483

P-1482

P-0333

P-1478

P-1477

P-1481

P-1590

P-1600

P-1603

P-1605

Example 25 Synthesis of3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid ethylamide P-1630

Compound P-1630 was synthesized in six steps from5-bromo-1-triisopropylsilyl-7-azaindole 68 as shown in Scheme 45.

Step 1—Preparation of1-Triisopropylsilanyl-1-pyrrolo[2,3-b]pyridine-5-carboxylic acid methylester (531)

To 5-bromo-1-triisopropylsilyl-7-azaindole (68, 1.50 g, 4.2 mmol,prepared as described in Example 6) in tetrahydrofuran (20.0 mL) underan atmosphere of nitrogen, cooled with dry ice/acetone, was slowly addedn-Butyllithium (10.0 M in hexane, 0.467 mL). After 60 minutes, methylchloroformate (0.394 mL, 5.1 mmol) was added to the reaction. Afteranother hour, the reaction was poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated to give the crude compoundas a light yellow solid that was used directly in the next step.

Step 2—Preparation of 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methylester (532)

To 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acidmethyl ester (531, 0.950 g, 2.9 mmol) in tetrahydrofuran (20.0 mL) wasadded tetrabutyl-ammonium fluoride, trihydrate (1.20 g, 3.8 mmol). Thereaction was stirred at room temperature for 10 minutes. The reactionwas concentrated and purified with silica gel column chromatographyeluting with 4% methanol in methylene chloride to give the compound as awhite solid (532, 300 mg, 60%). MS (ESI) [M+H⁺]⁺=177.2.

Step 3—Preparation of3-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid methyl ester (P-1545)

To 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (532, 155.0mg, 0.88 mmol) in methanol (15.0 mL) were added propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide (73, 260.0 mg, 0.99 mmol, preparedas described in Example 7) and potassium hydroxide (859 mg, 15.3 mmol)under an atmosphere of nitrogen. The reaction was stirred at roomtemperature overnight. The reaction was poured into water and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 20% ethyl acetate inhexane to give the compound as white solid (P-1545, 110 mg, 28%). MS(ESI) [M+H⁺]⁺=440.2.

Step 4—Preparation of3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid methyl ester (P-1552)

To3-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid methyl ester (P-1545, 100.0 mg, 0.23 mmol) in tetrahydrofuran (10mL) was added Dess-Martin periodinane (107 mg, 2.5 mmol). The reactionwas stirred at room temperature for 10 minutes. The reaction mixture wasconcentrated with silica gel and then purified with silica gel columnchromatography eluting with 30% ethyl acetate in hexane to give thecompound as white solid (P-1552, 80 mg, 80%). MS (ESI) [M+H⁺]⁺=438.2.

Step 5—Preparation of3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (P-1559)

To3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid methyl ester (P-1552, 80.0 mg, 0.18 mmol) in tetrahydrofuran (10.0mL) were added water (3.0 ml) and lithium hydroxide (82 mg, 3.4 mmol).The reaction was stirred at room temperature overnight. The reaction waspoured into water, acidified with 1 N HCl to pH around 1, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, filtered, concentrated, and washed with ethyl acetate to givean off-white solid (P-1559, 60 mg, 77%) MS (ESI) [M+H⁺]⁺=424.2.

Step 6: Preparation of3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1-pyrrolo[2,3-b]pyridine-5-carboxylicacid ethylamide (P-1630)

To3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (P-1559, 38.0 mg, 0.090 mmol) in tetrahydrofuran (2.3 mL) was addeda solution of ethylamine (2.0 M in tetrahydrofuran, 0.20 mL),bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (80.0 mg, 0.17mmol) and triethylamine (0.30 mL, 2.2 mmol) under an atmosphere ofnitrogen. The reaction mixture was stirred overnight at roomtemperature. The reaction was poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 40% ethyl acetate in hexane to givethe compound as a white solid (P-1630, 13.2 mg, 33%). MS (ESI)[M−H⁺]⁺=449.0.

Example 26 Synthesis of1-butyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-ureaP-1445

Compound P-1445 was synthesized in six steps from5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 as shown in Scheme 49.

Step 1—Preparation of(3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1399)

To 3-nitrobenzaldehyde (534, 1.08 g, 7.17 mmol) in methanol (34 mL) wasadded 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 1.08 g, 5.52 mmol,prepared as described in Example 17) and potassium hydroxide (1.55 g,27.6 mmol). The reaction was stirred at room temperature for four hours.The reaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated. The mixture was purified by silica gel columnchromatography eluting with 4% methanol in dichloromethane to providetwo different compounds, a white solid (P-1399, R═H, 1.20 g, 63%) MS(ESI) [M+H⁺]⁺=347.2, and a light yellow solid (535, R=Me, 0.434 g, 22%).

Step 2—Preparation of(3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(536)

To(3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1399, R═H, 500 mg, 1.44 mmol) in dimethylformamide (26 mL) was addedDess-Martin periodane (674 mg, 1.59 mmol). The reaction was stirred forone hour and the reaction was poured into water. All solids werefiltered and purified by silica gel column chromatography eluting with3% methanol in dichloromethane to give the compound (536, 295 mg, 59%).MS (ESI) [M+H⁺]⁺=345.2.

Step 3—Preparation of(3-nitro-phenyl)-[5-pyridin-3-yl-]-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(537)

To(3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(536, 291 mg, 0.85 mmol) in tetrahydrofuran (7 mL) was added 1.5 M oflithium diisopropylamide in cyclohexane (676 μl, 1.59 mmol) at −78° C.under an atmosphere of nitrogen. After 30 minutes, p-toluenesulfonylchloride (209 mg, 1.10 mmol) was added in tetrahydrofuran and thereaction was stirred for three hours. The reaction was poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated. All solidswere filtered and purified by silica gel column chromatography elutingwith 60% ethyl acetate in hexane to give the compound (537, 182 mg,43%). MS (ESI) [M+H⁺]⁺=499.2.

Step 4—Preparation of(3-Amino-phenyl)-[5-pyridin-3-yl-1H-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone(538)

To(3-nitro-phenyl)-[5-pyridin-3-yl-1H-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(537, 180 mg, 0.361 mmol) in methanol (4 mL) was added 10% palladium oncarbon (20 mg) and few drops of concentrated aqueous hydrochloric acid.The resulting mixture was stirred under an atmosphere of hydrogenovernight and the catalyst was filtered out through a bed of celite. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 90% ethyl acetate in hexane to give thecompound (538, 58 mg, 34%). MS (ESI) [M+H⁺]⁺=469.3.

Step 5—Preparation of1-Butyl-3-3-[5-pyridin-3-yl-1H-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl-urea(539)

To(3-Amino-phenyl)-[5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone(538, 53 mg, 0.11 mmol) in tetrahydrofuran (1.6 mL) was added1-isocyanatobutane (12 mg, 0.12 mmol). The reaction was heated at 90° C.overnight and it was concentrated and purified by silica gel columnchromatography eluting with 2% methanol in dichloromethane to give thecompound (539, 39 mg, 61%). MS (ESI) [M+H⁺]⁺=568.4.

Step 6—Preparation of1-Butyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea(P-1445)

To1-Butyl-3-3-[5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl-urea(539, 33 mg, 0.058 mmol) in tetrahydrofuran (2 mL) was added 1.0 Mtetra-n-butylammonium fluoride in tetrahydrofuran (192 μl) under anatmosphere of nitrogen and the reaction was stirred for three hours. Thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated. All solids were filtered and purified by silica gelcolumn chromatography eluting with 4% methanol in dichloromethane togive the compound (P-1445, 8 mg, 30%). MS (ESI) [M+H⁺]⁺=414.3.

Example 27 Synthesis of1-butyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-ureaP-1447

Compound P-1447 was synthesized in five steps from3-[(3-nitro-phenyl)-methoxy-methyl]-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine535 as shown in Scheme 50.

Step 1—Preparation of3-(3-nitro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1402)

-   To    3-[(3-nitro-phenyl)-methoxy-methyl]-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine    (535, 431 mg, 1.20 mmol, per Example 26, Scheme 49 Step 1) in    acetonitrile (130 mL), were added trifluoroacetic acid (18 mL, 230    mmol) and triethylsilane (36 mL, 230 mmol). The reaction was    refluxed for three hours. The reaction mixture was poured into    sodium bicarbonate solution and extracted with ethyl acetate. The    organic layer was washed with brine, dried over anhydrous sodium    sulfate and filtered. The filtrate was concentrated and purified by    silica gel column chromatography eluting with 80% ethyl acetate in    hexane to give the compound (P-1402, 323 mg, 82%).

MS (ESI) [M+H⁺]⁺=331.2.

Step 2—Preparation of3-(3-nitro-benzyl-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(552)

To 3-(3-nitro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1402,141 mg, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added sodiumhydride (60% dispersion in mineral oil, 21 mg, 0.512 mmol) under anatmosphere of nitrogen. After thirty minutes, p-toluenesulfonyl chloride(114 mg, 0.60 mmol) in N,N-dimethyl-formamide was added and the reactionwas stirred for three hours. The reaction was poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated. All solids werefiltered and purified by silica gel column chromatography eluting with40% ethyl acetate in hexane to give the compound (552, 120 mg, 58%). MS(ESI) [M+H⁺]⁺=485.25.

Step 3—Preparation of3-[5-Pyridin-3-yl-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenylamine(553)

To3-(3-nitro-benzyl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(552, 230 mg, 0.14 mmol) in methanol (5 mL) was added 10% palladium oncarbon (10 mg) and few drops of concentrated aqueous hydrochloric acid.The resulting mixture was stirred under an atmosphere of hydrogenovernight, and the catalyst was filtered out through a bed of celite.The filtrate was concentrated and purified by silica gel columnchromatography eluting with 90% ethyl acetate in hexane to give thecompound (553, 88 mg, 41%). MS (ESI) [M+H⁺]⁺=455.3.

Step 4—Preparation of1-butyl-3-3-[5-pyridin-3-yl-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenyl-urea(554)

To3-[5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenylamine(553, 14 mg, 0.031 mmol) in tetrahydrofuran (0.5 mL) was added1-isocyanatobutane (3.4 mg, 0.03 mmol). The reaction was heated at 90°C. overnight and was concentrated and purified by silica gel columnchromatography eluting with 2% methanol in dichloromethane to give thecompound (554, 7.2 mg, 42%). MS (ESI) [M+H⁺]⁺=554.4.

Step 5—Preparation of1-Butyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3ylmethyl)-phenyl]-urea (P-1447)

To1-butyl-3-3-[5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-phenyl-urea(554, 11 mg, 0.02 mmol) in tetrahydrofuran (0.7 mL) was added 1.0 Mtetra-n-butylammonium fluoride in tetrahydrofuran (66 μl) under anatmosphere of nitrogen and the reaction was stirred for three hours. Thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated. All solids were filtered and purified by silica gelcolumn chromatography eluting with 4% methanol in dichloromethane togive the compound (P-1447, 2.5 mg, 31%). MS (ESI) [M+H⁺]⁺=400.3.

1-Cyclopentyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-ureaP-1446

was prepared following the protocol of Scheme 50, substituting1-isocyanatobutane with isocyanato-cyclopentane in Step 4. MS (ESI)[M+H⁺]⁺=412.4.

Example 28 Synthesis of3-[3-chloro-4-(4-chloro-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridineP-1449

Compound P-1449 was synthesized in three steps from3-chloro-4-hydroxy-benzaldehyde 556 as shown in Scheme 51.

Step 1—Preparation of 3-chloro-4-(4-chloro-benzyloxy)-benzaldehyde (558)

To acetonitrile (15.0 mL) were added 3-chloro-4-hydroxy-benzaldehyde(556, 0.6 g, 4 mmol), 4-chlorobenzyl bromide (557, 1.2 g, 6 mmol), andpotassium carbonate (0.9 g, 7 mmol). The reaction was heated to 150° C.for 10 minutes in a CEM Discover microwave instrument. The reaction waspoured into water, extracted with ethyl acetate, and washed with brine.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The desired compound was isolated by silica gel columnchromatography (ethyl acetate:hexanes) (558, 0.85 g, 76%).

Step 2—Preparation of3-[3-chloro-4-(4-chloro-benzyloxy)-phenyl]-methoxy-methyl-1H-pyrrolo[2,3-b]pyridine(559)

1H-Pyrrolo[2,3-b]pyridine (94, 0.3 g, 2.8 mmol) was mixed with3-chloro-4-(4-chloro-benzyloxy)-benzaldehyde (558, 0.8 g, 3 mmol),potassium hydroxide (0.9 g, 17 mmol) and methanol (90.0 mL). Thereaction was heated to 50° C. under an atmosphere of nitrogen for sixdays. After neutralization with 6N hydrochloric acid the reaction waspoured into water, extracted with ethyl acetate, and washed with brine.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The desired compound was isolated by silica gel columnchromatography (ethyl acetate:hexanes) to give a yellow solid (559, 0.6g, 41%). MS (ESI) [M+H⁺]⁺=413.2, 415.2 [M−H⁺]⁻=411.1, 413.1.

Step 3—Preparation of3-[3-chloro-4-(4-chloro-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine(P-1449)

3-[3-Chloro-4-(4-chloro-benzyloxy)-phenyl]-methoxy-methyl-1-pyrrolo[2,3-b]pyridine(559, 0.2 g, 0.6 mmol) was mixed with trifluoroacetic acid (0.226 mL, 3mmol), triethylsilane (0.4 mL, 3 mmol) and acetonitrile (5 mL). Thereaction was heated at 50° C. and stirred for two days. The reaction wasconcentrated. The residue was diluted with ethyl acetate and neutralizedwith 2M aqueous sodium hydroxide. The reaction was poured into water,extracted with ethyl acetate, and washed with brine. The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated. Thedesired compound was isolated by silica gel column chromatography (ethylacetate:hexanes) to give a yellow solid (P-1449, 0.0744 g, 33%). MS(ESI) [M+H⁺]⁺=383.2, 385.2.

Additional compounds were prepared following the protocol of Scheme 51,replacing 3-chloro-4-hydroxy-benzaldehyde 556 with an appropriatealdehyde and optionally replacing 4-chlorobenzyl bromide 557 with anappropriate benzyl halide in Step 1, and optionally replacing1H-pyrrolo[2,3-b]pyridine 94 with an appropriate azaindole in Step 2.The following compounds were made following this procedure:

-   3-[4-(4-chloro-benzyloxy)-2-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1450),-   3-[4-(4-Chloro-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1462),-   3-[4-(4-Chloro-benzyloxy)-3-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1466),-   3-[4-(4-Chloro-benzyloxy)-3-ethoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1470),-   3-[2-Chloro-4-(4-chloro-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1471),-   3-[4-(4-Chloro-benzyloxy)-3-trifluoromethoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1487),-   3-[4-(4-Chloro-benzyloxy)-3-methoxy-benzyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine    (P-1531),-   5-Chloro-3-[4-(4-chloro-benzyloxy)-3-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1532),-   3-[4-(4-Chloro-2-fluoro-benzyloxy)-3-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1544),-   3-[4-(2,4-Dichloro-benzyloxy)-3-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1568),-   3-[3-Methoxy-4-(4-methoxy-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1569),-   3-[3-Methoxy-4-(2,4,6-trifluoro-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1578),-   3-[4-(2,6-Dichloro-benzyloxy)-3-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1579), and    3-[3-Chloro-4-(4-chloro-benzyloxy)-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1616).    The following table indicates the aldehyde (Column 2), the benzyl    halide (Column 3), and the azaindole (Column 4) used to afford the    target compound (Column 5). Column 1 indicates the compound number    and column 6 the observed mass.

MS(ESI) Benzyl [M + H⁺]⁺ Aldehyde halide Azaindole Compound observed P-1450

379.2 381.2 P- 1462

349.1 351.2 P- 1466

397.2 399.2 P- 1470

393.2 395.2 P- 1471

383.1 385.1 P- 1487

433.2 435.2 P- 1531

409.2 P- 1532

413.1 P- 1544

397.2 P- 1568

413.1 415.1 416.2 P- 1569

375.2 P- 1578

399.2 397.1 ([M − H⁺]⁻) P- 1579

413.2 415.2 416.2 ([M − H⁺]⁻) P- 1616

413.1

Example 29 Synthesis of3-(4-benzyloxy-3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine P-1613

Compound P-1613 was synthesized in two steps from4-benzyloxy-3-methoxy-benzaldehyde 564 as shown in Scheme 53.

Step 1—Preparation of3-[(4-benzyloxy-3-methoxy-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine(565)

Methanol (125 mL) and potassium hydroxide (4.4 g, 79 mmol) were mixedwith 1H-pyrrolo[2,3-b]pyridine (94, 3.1 g, 26.6 mmol) and4-benzyloxy-3-methoxy-benzaldehyde (564, 12.9 g, 53.2 mmol). Thereaction was stirred at room temperature for 2 days. The resulting whitesolid was filtered and washed with water. Crude material was carriedforward without further purification.

Step 2—Preparation of3-(4-benzyloxy-3-methoxy-benzyl-1H-pyrrolo[2,3-b]pyridine (P-1613)

3-[(4-Benzyloxy-3-methoxy-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine(565, 0.9 g, 2.4 mmol) and acetonitrile (50 mL) were mixed withtrifluoroacetic acid (0.360 mL, 4.7 mmol) and triethylsilane (0.746 mL,4.7 mmol). The reaction was heated at 80° C. and stirred overnight. Thereaction was concentrated. The mixture was extracted with ethyl acetateand saturated sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The desiredcompound was isolated by silica gel column chromatography to give thecompound (P-1613, 0.454 g 54.8%). MS (ESI) [M+H⁻]⁺=345.3.

Example 30 Synthesis of1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-butyl-ureaP-1596

Compound P-1596 was synthesized in one step from5-bromo-1H-pyrrolo[2,3-b]pyridine 67 as shown in Scheme 55.

Step 1—Preparation of1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-butyl-urea(P-1596)

To aluminum trichloride (3.67 g, 0.0275 mol) in dichloromethane (100 mL,2 mol) under an atmosphere of nitrogen was added 5-bromo-7-azaindole(67, 1.08 g, 0.00548 mol) at room temperature. After one hour,3-isocyanato-benzoyl chloride (584, 5.00 g, 0.0275 mol) was added underan atmosphere of nitrogen at room temperature. The resulting mixture wasstirred over night at room temperature. 1-Butanamine (585, 54 mL, 0.54mol) was added carefully. All solvents were removed. The residue waspurified by silica gel column chromatography to give the compound(P-1596, 172 mg, 8%). MS (ESI) [M−H+]−=413.1, 415.0.

Additional compounds were prepared following the protocol of Scheme 55,replacing 1-butanamine 585 with an appropriate amine and optionallyreplacing 5-bromo-7-azaindole 67 with5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 (prepared as described inExample 17). The following compounds were made following this procedure:

-   1-Benzyl-3-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1553),-   1-Benzyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1554),-   1-(2-Methoxy-ethyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1566), and-   1-Phenyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1591).    The following table indicates the amine (column 2) and the azaindole    (column 3) used to afford the target compound (column 4). The    compound number is provided in column 1 and the observed mass in    column 5.

MS(ESI) [M + H⁺]⁺ Amine Azaindole Compound observed P-1553

447.0 449.1 P-1554

448.3 P-1566

416.3 P-1591

434.3

Example 31 Synthesis of1-Butyl-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl-ureaP-1880

Compound P-1880 was synthesized in one step from1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-butyl-ureaP-1596 as shown in Scheme 56.

Step 1—Preparation of1-Butyl-3-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl-urea(P-1880)

In a microwave tube,1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-butyl-urea(P-1596, 0.077 g, 0.00018 mol, prepared as described in Example 30,Scheme 55),1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(0.0964 g, 0.000464 mol), and Tetrakis(triphenylphosphine)palladium(0)(0.011 g, 0.0000093 mol) were mixed in 1.00 M of potassium carbonate inwater (1.2 mL), acetonitrile (2.0 mL, 0.037 mol), and tetrahydrofuran(1.0 mL, 0.012 mol). The resulting mixture was heated at 100° C. in themicrowave for 20 minutes, then at 120° C. for 10 minutes. The reactionwas poured into water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography to give the compound (P-1880, 52 mg, 67%). MS(ESI) [M+H⁺]⁺=417.4.

Example 32 Synthesis of1-Butyl-3-[2-chloro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ureaP-1828

Compound P-1828 was synthesized in two steps from3-amino-2-chlorobenzoic acid 586 as shown in Scheme 57.

Step 1—Preparation of 1-(3-Butyl-ureido-2-chloro-benzoic acid (587)

To N,N-diisopropylamine (1.72 mL, 0.0122 mol) in tetrahydrofuran (12 mL,0.14 mol), was added 1.6 M n-butyllithium in hexane (7.6 mL) at −78° C.under an atmosphere of nitrogen. After 30 minutes,3-amino-2-chlorobenzoic acid (586, 1.00 g, 0.00583 mol) was added. Afteranother 30 minutes, 1-isocyanatobutane (2.60 mL, 0.0233 mol) was addedat −78° C. under an atmosphere of nitrogen and allowed to stir for twohours. The reaction mixture was warmed up to room temperature andstirred at room temperature for 30 minutes, The reaction was quenchedwith 1M HCl (aqueous) solution and extracted with ethyl acetate twice.The combined organic layers were washed with brine, dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting withdichloromethane:methanol:acetic acid 40:2:1 to give the compound as anoff-white solid (587, 147 mg, 9%).

Step 2—Preparation of1-Butyl-3-[2-chloro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea(P-1828)

To 3-(3-Butyl-ureido)-2-chloro-benzoic acid (587, 103 mg, 0.000380 mol)was added dichloromethane (10 mL, 0.2 mol) followed by thionyl chloride(110mL, 0.0015 mol) and 1 drop of dimethylformamide to give asuspension. The reaction was stirred at room temperature for 2 hours.Solid material was still present in the reaction mixture, sotetrahydrofuran (0.5 mL, 0.006 mol) was added and continued stirring atroom temperature. The reaction became a clear solution after 2 hours,then stirred for another hour. All volatiles were removed under vacuumand the residue stripped from toluene, twice. The solid was then driedunder high vacuum for 60 minutes and dissolved in dichloromethane (5mL). This was added to 5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (89,0.074 g, 0.00038 mol, prepared as described in Example 17) which hadbeen treated with aluminum trichloride (0.25 g, 0.0019 mol) indichloromethane (10 mL) for 1 hour. The reaction was stirred at roomtemperature overnight, then quenched with methanol (5 mL). The resultingsolution was extracted with ethyl acetate and water with added saturatedsodium bicarbonate to adjust pH 8. The organic layer was washed withsodium bicarbonate and brine and dried over magnesium sulfate andfiltered. The organic layer was concentrated and purified by silica gelcolumn chromatography eluting with 2% methanol in dichloromethanefollowed by 5% methanol in dichloromethane to give the compound as awhite solid (P-1828, 45 mg, 26%).

MS (ESI) [M+H⁺]⁺=448.3.

Additional compounds were prepared following the protocol of Scheme 57,replacing 3-amino-2-chlorobenzoic acid 586 with an appropriatecarboxylic acid and optionally replacing 1-isocyanatobutane with anappropriate isocyanate in Step 1 and optionally replacing5-(pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridine 89 with an appropriatesubstituted 7-azaindole (see Example 17) in Step 2. The followingcompounds were made following this procedure:

-   1-Butyl-3-[2-methyl-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1742),-   3-Butyl-1-methyl-1-[2-methyl-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1855),-   [3-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-urea    (P-1570),-   [4-Fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1589),-   3-{3-[5-(3-Butyl-ureido)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide    (P-1621),-   1-Butyl-3-{4-fluoro-3-[5-(3-methane    sulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1627), and-   1-[3-(5-Bromo-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-butyl-urea    (P-1637).    The following table indicates the carboxylic acid (column 2), the    isocyanate (column 3), and the azaindole (column 4) used to afford    the target compound (column 5). Column 1 indicates the compound    number and column 6 the observed mass.

MS(ESI) Iso- [M + H⁺]⁺ Acid cyanate Azaindole Compound observed P- 1742

428.3 P- 1855

442.3 P- 1570

HN═C═O

377.1 379.1 P- 1589

HN═C═O

375.2 P- 1621

474.3 P- 1627

509.2 P- 1637

433.1 435.1

Example 33 Synthesis of1-Butyl-3-[4-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea(P-1534)

Compound P-1534 was synthesized in two steps from5-(3-butylureido)-2-fluorobenzoic acid 588 (prepared from3-fluoro-5-aminobenzoic acid and 1-isocyanatobutane following theprotocol described in Step 1 of Scheme 57, Example 32) and5-bromo-7-azaindole 67 as shown in Scheme 58.

Step 1—Preparation of1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-butyl-urea(P-1637)

To aluminum trichloride (0.524 g, 0.00393 mol) and dichloromethane (20mL, 0.3 mol) under an atmosphere of nitrogen was added5-bromo-7-azaindole (67, 0.155 g, 0.000787 mol) in dichloromethane. To5-(3-butylureido)-2-fluorobenzoic acid (588, 0.200 g, 0.000787 mol) wasadded 4 mL of dichloromethane (4 mL) followed by thionyl chloride (69μL, 0.00094 mol) and a drop of N,N-dimethylformamide. After 1 hour, thereaction remained a suspension so additional thionyl chloride was addedalong with tetrahydrofuran. The reaction remained a suspension, so wasplaced in a 50° C. oil bath. After another hour, the reaction was stilla suspension, and so was left to react at 50° C. overnight. The reactionhad become a clear solution. All volatiles were removed under vacuum,then the residue dissolved in dichloromethane and added to the5-bromo-7-azaindole and aluminum trichloride suspension. The reactionwas allowed to stir at room temperature for 4.5 hours, followed by theaddition of water and extraction with ethyl acetate. The organic layerwas dried over magnesium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith a gradient of methanol (0 to 10%) in dichloromethane to give thecompound (P-1637, 14 mg, 4%).

Step 2—Preparation of1-Butyl-3-[4-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea(P-1534)

To1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-butyl-urea(P-1637, 14.0 mg, 0.0000323 mol), 3-pyridylboronic acid (5.96 mg,0.0000485 mol), and Tetrakis(triphenylphosphine)palladium(0) (0.820 mg,7.09E-7 mol) were mixed in 1.00 M potassium carbonate in water (1.00 mL)and acetonitrile (2.00 mL, 0.0383 mol). The resulting mixture was heatedat 120° C. in the microwave for 40 minutes. The reaction was extractedwith ethyl acetate and water twice, and the combined organic layers werewashed with 1M sodium bicarbonate followed by brine and the organiclayer was dried over magnesium sulfate and filtered. The organic layerwas concentrated and purified by reverse phase HPLC (acetonitrile andwater with 0.1% formic acid) to give the compound as a white solid(P-1637, 8.5 mg, 61%). MS (ESI) [M+H⁺]⁺=432.3.

1-Butyl-3-{4-fluoro-3-[5-(3-trifluoromethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-ureaP-1660

was prepared following the protocol of Scheme 58, replacing3-Pyridylboronic acid with 3-trifluoromethoxy-phenylboronic acid in Step2. MS (ESI) [M+H⁺]⁺=515.2.

Example 34 Synthesis of Aldehyde Reagents for Coupling to 7-Azaindoles

Aldehyde compounds for coupling to the 3-position of a 7-azaindole areshown in the following Schemes.3-Methoxy-4-[4-(4-methyl-piperazin-1-ylmethyl)-benzyloxy]-benzaldehyde591 was prepared in one Step as shown in Scheme 59.

Step 1—Synthesis of3-Methoxy-4-[4-(4-methyl-piperazin-1-ylmethyl)-benzyloxy]-benzaldehyde(591)

To 4-Hydroxy-3-methoxybenzaldehyde (105, 2.1 g, 0.014 mol) inN,N-dimethylformamide (40.0 mL) were added 1,4-bis(bromomethyl)-benzene(589, 4.00 g, 0.0152 mol) and potassium carbonate (5.0 g, 0.036 mol)under an atmosphere of nitrogen. After 12 hours 1-methyl-piperazine(590, 3.8 mL, 0.034 mol) was added to the reaction. After 2 hours, thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% methanol in dichloromethane to give thecompound (589, 1.2 g, 25.0%). MS (ESI) [M+H⁺]⁺=355.3.

2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde 593 was synthesized in onestep from 2-fluoro-4,5-dimethoxy-benzaldehyde 592 as shown in Scheme 60.

Step 1—Synthesis of 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (593)

To 2-fluoro-4,5-dimethoxy-benzaldehyde (592, 1.00 g, 5.43 mol) indichloromethane (50.0 mL) was added aluminum trichloride (4.34 g, 32.6mmol) under an atmosphere of nitrogen. The reaction was stirred at roomtemperature overnight. The reaction was poured into water and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and washed withethyl acetate and hexane to give a white solid (593, 0.70 g, 76.0%).

2,5-Difluoro-4-hydroxy-benzaldehyde 597 was synthesized in three stepsfrom 2,5-difluorophenol 594 as shown in Scheme 61.

Step 1—Synthesis of 4-bromo-2,5-difluoro-phenol (595)

To 2,5-difluorophenol (594, 5.50 g, 0.0423 mol) in chloroform (110.0mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, thereaction was poured into a solution of sodium thiosulfate and extractedwith ethyl acetate. The organic layer was dried over sodium sulfate,concentrated and purified with silica gel column chromatography elutingwith 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g,70.2%).

Step 2-(4-Bromo-2,5-difluoro-phenoxy-tert-butyl-dimethyl-silane (596)

To 4-bromo-2,5-difluoro-phenol (595, 3.50 g, 0.0167 mol) inN,N-dimethylformamide (50.0 mL) were added tert-butyldimethylsilylchloride (3.83 g, 0.0254 mol) and 1H-imidazole (6.00 g, 0.0529 mol). Thereaction was stirred at room temperature overnight, then poured intowater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 20% ethylacetate in hexane to give the compound (596, 3.0 g, 55.4%).

Step 3-2,5-Difluoro-4-hydroxy-benzaldehyde (597)

To (4-bromo-2,5-difluoro-phenoxy)-tert-butyl-dimethyl-silane (596, 3.00g, 9.28 mmol) in tetrahydrofuran (37.5 mL), under an atmosphere ofnitrogen at −78° C., n-butyllithium (3.90 mL, 2.50 M in hexane) wasadded slowly. After 30 minutes, N,N-dimethylformamide (0.825 mL, 0.0106mol) was added to the reaction. One hour later, the reaction was allowedto come to room temperature. The reaction was poured into water and 1 NHCl, then extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 20% ethylacetate in hexane to give the compound as an off-white solid (597, 0.86g, 59.0%).

4-(4-Chloro-benzyloxy)-3-fluoro-benzaldehyde 599 was synthesized in onestep from 3-fluoro-4-hydroxy-benzaldehyde 598 as shown in Scheme 62.

Step 1—Synthesis of 4-(4-chloro-benzyloxy)-3-fluoro-benzaldehyde (599)

To 3-fluoro-4-hydroxy-benzaldehyde (598, 0.800 g, 5.71 mmol) inN,N-dimethylformamide (50.0 mL) was added sodium hydride (260.0 mg, 60%in mineral oil, 6.50 mmol). After 15 minutes, 4-chlorobenzyl bromide(557, 1.29 g, 6.28 mmol) was added to the reaction mixture. The reactionwas stirred at 80° C. for 5 hours. The reaction was poured into waterand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 30% ethylacetate in hexane to give the compound (599, 1.3 g, 86.0%).

Additional aldehydes were prepared using the protocol of Scheme 62,replacing either 4-chlorobenzyl bromide 557 with a suitable alkylatingagent, and/or 3-fluoro-4-hydroxy-benzaldehyde 598 with a suitablealdehyde. The following table indicates the alkylating agent (column 1)and the starting aldehyde (column 2) used to afford the aldehyde (column3) synthesized following this protocol.

Alkylating agent Aldehyde Compound

Example 35 Synthesis of[4-(4-chloro-benzyloxy)-3-fluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1897 and related compounds

Compound P-1897 was synthesized in two steps from4-(4-chloro-benzyloxy)-3-fluoro-benzaldehyde 599 as shown in Scheme 63.

Step 1—Synthesis of[4-(4-chloro-benzyloxy)-3-fluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1895)

To 1H-Pyrrolo[2,3-b]pyridine (94, 100.0 mg, 0.85 mmol) in methanol (50.0mL) were added 4-(4-chloro-benzyloxy)-3-fluoro-benzaldehyde (599, 250.0mg, 0.94 mmol, prepared as described in Example 34) and potassiumhydroxide (1.00 g, 17.82 mmol) under an atmosphere of nitrogen. Thereaction was stirred at room temperature overnight. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 30% ethyl acetate in hexane to give the compound (P-1895, 55 mg,17.0%). MS (ESI) [M+H⁺]⁺=383.3.

Step 2—Synthesis of[4-(4-chloro-benzyloxy)-3-fluoro-phenyl]-(H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1897)

To[4-(4-chloro-benzyloxy)-3-fluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1895, 17.7 mg, 0.046 mmol) in tetrahydrofuran (10.0 mL) was addedDess-Martin periodinane (23.5 mg, 0.056 mmol). The reaction was stirredat room temperature for 15 minutes. The reaction was concentrated, thenpurified with silica gel column chromatography eluting with 50% ethylacetate in hexane to give a white solid (P-1897, 6.4 mg, 36.3%). MS(ESI) [M+H⁺]⁺=381.3.

Additional compounds were prepared using the protocol of Scheme 63,replacing 4-4-(4-chloro-benzyloxy)-3-fluoro-benzaldehyde 599 with asuitable aldehyde (prepared as described in Example 34), and optionallyreplacing 1H-Pyrrolo[2,3-b]pyridine 94 with an appropriate substituted7-azaindole (see Example 9 or Example 16) in Step 1. The followingcompounds were made following this procedure:

-   [4-(4-Chloro-benzyloxy)-2-fluoro-5-methoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1845),-   [4-(4-Chloro-3-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1850),-   [4-(1H-Benzoimidazol-2-ylmethoxy)-3-fluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1900),-   (4-Benzyloxy-2,5-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1903),-   [4-(1H-Benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-phenyl]-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1979),-   [4-(1H-Benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1982),-   [4-(1H-3-Benzoimidazol-2-ylmethoxy)-2,5-difluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1987),-   {4-[2-(2-Bromo-ethoxy)-ethoxy]-2-fluoro-5-methoxy-phenyl}-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1988),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2,5-difluoro-4-(2-methoxy-ethoxy)-phenyl]-methanone    (P-1989), and-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-5-methoxy-4-(2-methoxy-ethoxy)-phenyl]-methanone    (P-1991).    The following table indicates the aldehyde (column 2) and the    azaindole (column 3) used to afford the target compound (column 4).    Column 1 indicates the compound number and column 5 the observed    mass.

MS(ESI) [M + H⁺]⁺ Aldehyde Azaindole Compound observed P-1845

409.6 [M − H⁺]⁻ P-1850

P-1900

387.4 P-1903

363.3 [M − H⁺]⁻ P-1979

447.4 P-1982

417.3 P-1987

405.3 P-1988

471.2 473.2 P-1989

365.2 [M − H⁺]⁻ P-1991

377.2 [M − H⁺]⁻

Example 36 Synthesis of3-(4-Benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine P-1901

Compound P-1901 was synthesized in four steps from4-bromo-2,5-difluoro-phenol 595 as shown in Scheme 64.

Step 1—Synthesis of 1-Benzyloxy-4-bromo-2, S-difluoro-benzene (600)

To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared asdescribed in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL)were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) andbenzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at roomtemperature overnight. The reaction was poured into water and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 5% ethyl acetate in hexaneto give a white solid (600, 0.84 g, 65.0%).

Step2-(4-Benzyloxy-2,5-difluoro-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(601)

To 1-Benzyloxy-4-bromo-2,5-difluoro-benzene (600, 0.84 g, 2.80 mmol) intetrahydrofuran (15.0 mL) and ether (15.0 mL), under an atmosphere ofnitrogen at −78° C., n-butyllithium (1.20 mL, 2.50 M in hexane) wasadded slowly. After 20 minutes,1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (96, 0.82g, 0.0027 mol, prepared as described in Example 18) was added to thereaction. After 20 minutes, the reaction was allowed to warm to roomtemperature for 10 minutes, then poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified with silica gelcolumn chromatography eluting with 20% ethyl acetate in hexane to awhite solid (601, 1.0 g, 70.0%). MS (ESI) [M+H⁺]⁺=523.4.

Step 3—Synthesis of(4-Benzyloxy-2,5-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1902)

To(4-Benzyloxy-2,5-difluoro-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(601, 1.00 g, 1.91 mmol) in tetrahydrofuran (15.0 mL) was addedtetrabutylammonium fluoride, trihydrate (0.63 g, 2.04 mmol). Thereaction was stirred at room temperature for 10 minutes. The reactionwas roto-evaporated and purified with silica gel column chromatographyeluting with 50% ethyl acetate in hexane to give the compound as a whitesolid (P-1902, 0.59 g, 84.0%). MS (ESI) [M+H⁺]⁺=367.4.

Step 4—Synthesis of3-(4-Benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1901)

To(4-Benzyloxy-2,5-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1902, 500.0 mg, 1.37 mmol) in acetonitrile (25.0 mL) were addedtriethylsilane (2.00 mL, 0.0125 mol) and trifluoroacetic acid (1.00 mL,0.0130 mol). The reaction was heated to reflux for 2 hours. The reactionwas concentrated and purified with silica gel column chromatographyeluting with 50% ethyl acetate in hexane to give a white solid (P-1901,60.0 mg, 94.1%). MS (ESI) [M+H⁺]⁺=351.4.

3-[3-Trifluoromethyl-4-(4-trifluoromethyl-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridineP-1797

was prepared using the protocol of Scheme 64, substituting4-bromo-2,5-difluoro-phenol 595 with 4-bromo-2-trifluoromethyl-phenol(prepared as described in Example 34, Scheme 61, Step 1, substituting2,5-difluoro-phenol 594 with 2-trifluoromethyl-phenol) and benzylbromide with 1-bromomethyl-4-trifluoromethyl-benzene in Step 1. MS (ESI)[M+H⁺]⁺=451.

Example 37 Synthesis of3-[4-(4-chloro-benzyloxy)-2,5-difluoro-benzyl]-1H-pyrrolo[2,3-b]pyridineP-1974

Compound P-1974 was synthesized in four steps from3-(4-benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine P-1901 asshown in Scheme 65.

Step 1—Synthesis of3-(4-Benzyloxy-2,5-difluoro-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(602)

To 3-(4-Benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine(P-1901, 560.0 mg, 1.60 mmol, prepared as described in Example 18,Scheme 33) in tetrahydrofuran (28.0 mL) was added sodium hydride (100.0mg, 60% in mineral oil, 2.50 mmol). After 10 minutes, triisopropylsilylchloride (0.500 mL, 2.36 mmol) was added to the reaction. After 4 hours,the reaction was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 30% ethyl acetate in hexane to give thecompound (602, 0.70 g, 86.1%).

Step 2—Synthesis of2,5-difluoro-4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol(603)

To3-(4-Benzyloxy-2,5-difluoro-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(602, 0.70 g, 0.0014 mol) in methanol (30.0 mL) was added 50% palladiumhydroxide on carbon (0.1 g) under an atmosphere of hydrogen. Thereaction was stirred at room temperature overnight. The reaction wasfiltered and concentrated to give a colorless oil (603, 0.47 g, 82.0%).

Step3-3-[4-(4-Chloro-benzyloxy)-2,5-difluoro-benzyl]-1-triisopropylsilanyl-1-pyrrolo[2,3-b]pyridine(604)

To2,5-difluoro-4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol(603, 120.0 mg, 0.29 mmol) in N,N-dimethylformamide (15.0 mL) was addedsodium hydride (18.0 mg, 60% in mineral oil, 0.45 mol) under anatmosphere of nitrogen. After 10 minutes, 4-chlorobenzyl bromide (65.1mg, 0.32 mol) was added to the reaction. The reaction was stirred at 40°C. overnight. The reaction was poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to give the crudecompound (604, 0.15 g) that was used directly in the next step.

Step 4-Synthesis of3-[4-(4-chloro-benzyloxy)-2,5-difluoro-benzyl]-1H-pyrrolo[2,3-b]pyridine(P-1974)

To3-[4-(4-chloro-benzyloxy)-2,5-difluoro-benzyl]-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(604, 0.150 g, 0.28 mmol) in tetrahydrofuran (10.0 mL) was addedtetra-n-butylammonium fluoride (80.0 mg, 0.31 mmol). After 10 minutes,the reaction was concentrated and purified by silica gel columnchromatography eluting with 50% ethyl acetate in hexane to give thecompound as a white solid (P-1974, 30.8 mg, 28.9%). MS (ESI)[M+H⁺]⁺=385.3.

2-[2,5-Difluoro-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxymethyl]-1H-benzoimidazoleP-1975

was prepared using the protocol of Scheme 65, substituting4-chlorobenzyl bromide with 2-chloromethyl-1H-benzoimidazole in step 3.MS (ESI) [M+H⁺]⁺=391.3.

Example 38 Synthesis of1-(4-Butoxy-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-ureaP-1754

Compound P-1754 was synthesized in three steps from5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine 605 as shown in Scheme 66.

Step 1—Preparation of(3-chloro-phenyl)-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone(606)

To 5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine (605, 530 mg, 2.5 mmol,prepared as described in Example 23) dissolved in 20 mL of dioxane wasadded 3-nitrobenzaldehyde (534, 758 mg, 5 mmol) and potassium hydroxide(4 mL of 2.5M aqueous). The vial was shaken on an orbital shaker for 16hrs and the dioxane was removed under reduced pressure. The residue waspartitioned between ethyl acetate and water. The aqueous layer wasneutralized with the addition of 1M HCl. The organic layer was washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure to give yellow-orange oil (1.5 g). The crude material wasdissolved in dichloromethane (150 mL) and chilled to 0° C. With vigorousstirring, pyridinium chlorochromate (3.0 g, 14 mmol) was added slowly,maintaining the solution temperature at 0° C. After complete additionthe solution was allowed to stir at ambient temperature for 1 hour. Theresulting dark brown/black solution was diluted with chloroform andpassed through a plug of silica. Elution with methanol gave 1.5 g ofcrude 606 that was carried on to the next step without furtherpurification.

Step 2—Preparation of(3-Amino-phenyl)-[5-(4-fluoro-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone(607)

Crude(3-chloro-phenyl)-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone(606, 1.5 g) was dissolved in a minimal amount of methanol (˜5 mL) andPd/C (5%, ˜10 mg) was added. The reaction mixture was shaken on a Parrshaker under 70 psi H₂ overnight. The reaction mixture was filteredthrough Celite® and concentrated under reduced pressure to give 1.4 g ofcrude 607 that was carried on to the next step without furtherpurification.

Step 3—Preparation of1-(4-Butoxy-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea(P-1754)

To a solution of(3-Amino-phenyl)-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone(607, 7.5 mg) in anhydrous pyridine (200 μL) was added neat1-butoxy-4-isocyanato-benzene (608, 1.6 mg) and the reaction mixture wasstirred at ambient temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inDMSO (200 μL) and purified using reverse phase HPLC with anacetonitrile/water gradient. MS (ESI) [M+H⁺]⁺=523.5.

Additional compounds were prepared following the protocol of Scheme 66,optionally substituting 5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine605 with a suitable azaindole in Step 1 and or optionally substituting1-butoxy-4-isocyanato-benzene 608 with a suitable isocyanate in Step 3.Azaindoles were purchased or prepared as described in Examples 9 or 17.The following compounds were prepared by this procedure:

-   1-(2-Methoxy-ethyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1566),-   1-Phenyl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1591),-   1-Phenyl-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1703),-   1-(4-Fluoro-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1704),-   1-(4-Methoxy-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1705),-   1-(3,4-Difluoro-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1706),-   1-(3-Methoxy-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1707),-   1-(3,4-Dimethoxy-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1708),-   1-(4-Chloro-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1709),-   1-(3-Chloro-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1710),-   1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1711),-   1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1712),-   1-(2-Chloro-4-trifluoromethyl-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1713),-   1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1714),-   1-(4-Butoxy-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1715),-   1-(3-Fluoro-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1716),-   1-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea    (P-1717),-   1-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-p-tolyl-urea    (P-1718),-   1-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-m-tolyl-urea    (P-1719),-   1-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-o-tolyl-urea    (P-1720),-   1-(4-Methoxy-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1723),-   1-(3,4-Difluoro-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1724),-   1-(3,4-Dimethoxy-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1725),-   1-(3-Chloro-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1726),-   1-(2-Chloro-4-trifluoromethyl-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]-urea    (P-11727),-   1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1728),-   1-(4-Butoxy-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1729),-   1-(3-Fluoro-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1730),-   1-[3-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea    (P-1731),-   1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1732),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-phenyl]-urea    (P-1733),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(4-methoxy-phenyl)-urea    (P-1734),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(3,4-difluoro-phenyl)-urea    (P-1735),-   1-(3-Chloro-phenyl)-3-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1736),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea    (P-1737),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(2-chloro-5-trifluoromethyl-phenyl)-urea    (P-1738),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3(2-chloro-4-trifluoromethyl-phenyl)-urea    (P-1739),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(2-fluoro-3-trifluoromethyl-phenyl)-urea    (P-1740),-   1-(4-Butoxy-phenyl)-3-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1741),-   1-[3-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea    (P-1746),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea    (P-1747),-   1-(4-Fluoro-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1748),-   1-(3-Methoxy-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1749),-   1-(4-Chloro-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1750),-   1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1751),-   1-(2-Chloro-5-trifluoromethyl-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1752),-   1-(2-Chloro-4-trifluoromethyl-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1753).-   1-(4-Butoxy-phenyl)-3-{3-[5-(4-Fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1754),-   1-[3-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea    (P-1755),-   1-[3-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-p-tolyl-urea    (P-1756),-   1-[3-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-m-tolyl-urea    (P-1757),-   1-{3-[5-(4-Fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-m-tolyl-urea    (P-1758),-   1-[3-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-o-tolyl-urea    (P-1759),-   1-Pyridin-4-yl-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1760),-   1-(2-Methoxy-ethyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1761),-   1-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1762),-   1-(6-Methoxy-pyridin-3-yl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1763),-   1-Isoxazol-3-yl-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1764).-   1-(3-Methyl-isoxazol-5-yl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1765),-   1-[3-Chloro-4-trifluoromethyl-phenyl])-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1766),-   1-(3,4-Dimethyl-isoxazol-5-yl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1767),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-pyridin-4-yl-urea    (P-1770),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-pyridin-3-yl-urea    (P-1771),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(2-methoxy-ethyl)-urea    (P-1772),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(3-methoxy-5-trifluoromethyl-phenyl)-urea    (P-1773),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(6-methoxy-pyridin-3-yl)-urea    (P-1774),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-isoxazol-3-yl-urea    (P-1775),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(3,4-dimethyl-isoxazol-5-yl)-urea    (P-1776),-   1-Pyridin-4-yl-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1777),-   1-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1778),-   1-(6-Methoxy-pyridin-3-yl)-3-[3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1779),-   1-(4-Dimethylamino-phenyl)-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1780),-   1-Pyridin-3-yl-3-[3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-urea    (P-1781),-   1-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-(4-dimethylamino-phenyl)-urea    (P-1782),-   1-(4-Fluoro-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1816),-   1-(3,4-Difluoro-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1817),-   1-(3,4-Dimethoxy-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1818), and-   1-(3-Fluoro-phenyl)-3-{3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-urea    (P-1819).    The following table indicates the azaindole (column 2) and    isocyanate (column 3) used to afford the target compound (column 4).    Column 1 provides the compound number and the observed mass is given    in column 5.

MS(ESI) [M + H⁺]⁺ Azaindole Isocyanate Compound observed P-1566

416.3 P-1591

434.3 P-1703

357.1 P-1704

375.1 P-1705

387.1 P-1706

393.1 P-1707

387.1 P-1708

417.5 P-1709

391.1 P-1710

391.1 P-1711

459.1 P-1712

459.1 P-1713

459.1 P-1714

443.1 P-1715

429.1 P-1716

375.1 P-1717

425.1 P-1718

371.1 P-1719

371.1 P-1720

371.1 P-1723

463.9 P-1724

470.3 P-1725

494.3 P-1726

468.3 P-1727

535.9 P-1728

520.3 P-1729

505.9 P-1730

451.9 P-1731

502.3 P-1732

535.9 P-1733

391.1 P-1734

421.1 P-1735

427.1 P-1736

425.1 P-1737

493.1 P-1738

493.1 P-1739

493.1 P-1740

477.1 P-1741

463.1 P-1746

425.1 P-1747

459.1 P-1748

451.9 P-1749

463.9 P-1750

467.9 P-1751

535.9 P-1752

553.2 P-1753

553.2 P-1754

523.5 P-1755

502.3 P-1756

447.9 P-1757

447.9 P-1758

465.1 P-1759

447.9 P-1760

358.3 P-1761

339.1 P-1762

455.1 P-1763

388.3 P-1764

348.3 P-1765

362.3 P-1766

459.1 P-1767

376.3 P-1770

392.3 P-1771

392.3 P-1772

373.1 P-1773

489.1 P-1774

421.9 P-1775

382.3 P-1776

410.3 P-1777

435.1 P-1778

531.9 P-1779

465.1 P-1780

400.3 P-1781

358.3 P-1782

434.3 P-1816

468.1 P-1817

486.1 P-1818

510.2 P-1819

468.1

Example 39 Synthesis ofN-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-difluorobenzenesulfonamideP-1841

Compound P-1841 was synthesized in six steps from 2,4-difluoroaniline 42as shown in Scheme 67,

Step 1—Preparation of (2,4-difluoro-phen-carbamic acid benzyl ester(613)

To 2,4-difluoroaniline (42, 7.0 mL, 0.070 mol) in 100 mL ofdichloromethane was added pyridine (11 mL, 0.14 mol) and benzylchloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred atambient temperature for 1.5 hours. The reaction mixture was concentratedunder reduced pressure and the residue was partitioned between ethylacetate and KHSO₄ solution. The organic layer was dried (MgSO₄),concentrated and crystallized from hexanes to give compound 613 (15.6 g,85%).

Step 2—Preparation of (2,4-difluoro-3-formyl-phenyl)-carbamic acidbenzyl ester (614)

Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acidbenzyl ester (613, 3.83 g, 14.5 mmol) in tetrahydrofuran (148 mL, 1.82mol). The solution was chilled to −78° C. and n-butyllithium (1.60 M inhexane, 19.1 mL, 30.0 mmol) was added over 30 minutes followed by theaddition of, N,N-dimethylformamide (1.12 mL, 14.5 mol). The reactionmixture was allowed to warm to ambient temperature and was stirredovernight. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, concentrated and crystallized from ether to givecompound 614 (3.0 g, 71%).

Step 3—Preparation of{2,4-difluoro-3-[hydroxy-(H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid benzyl ester (615)

Into a round bottom flask was added 5-chloro-1H-pyrrolo[2,3-b]pyridine(80, 0.524 g, 3.43 mmol, prepared as described in Example 9) in methanol(5.00 mL, 0.123 mol). Potassium hydroxide (0.800 g, 14.2 mmol) and(2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (614, 1.02 g,3.5 mmol) were added and the reaction mixture was stirred overnight. Thereaction mixture was poured into 1N HCl and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, concentrated and crystallized from ethyl acetate to givecompound 615 (710 mg, 46%). MS (ESI) [M+H⁺]⁺=444.

Step 4—Preparation of2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl-phenyl-carbamicacid benzyl ester (616)

Into a round bottom flask was added{2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-carbamicacid benzyl ester (615, 1.01 g, 2.28 mmol) in tetrahydrofuran (5.00 mL,0.0616 μmol). Dess-Martin periodinane (1.20 g, 2.89 mmol) was added inportions. The reaction mixture was stirred at ambient temperature for 10minutes, then poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate,concentrated and purified by silica gel chromatography to give compound616 (914 mg, 910%). MS (ESI) [M+H⁺]⁺=442.

Step 5—Preparation of(3-Amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1801)

[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-carbamicacid benzyl ester (616, 800 mg, 1.81 mmol) was added to 10 M NaOH (15.00mL) and warmed to reflux overnight. The reaction mixture was dilutedwith 30 mL of water and was extracted with ethyl acetate to givecompound P-1801 (450 mg, 81%).

Step 6—Preparation ofN-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-difluorobenzenesulfonamide(P-1841)

Into a microwave reaction vessel were combined(3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1801, 50 mg, 0.16 mmol), 3,5-difluorobenzenesulfonyl chloride (610,103 mg, 0.49 mmol), pyridine (0.5 mL, 6.1820 mol) and tetrahydrofuran(3.0 mL). The reaction was warmed in the CEM microwave at 300 watts,130° C. for 10 minutes. The reaction mixture was partitioned betweenethyl acetate and brine. The organic layer was collected, dried overNa₂SO₄, filtered and concentrated. The compound (P-1841) was isolatedusing column chromatography (silica, hexane:ethyl acetate 70:30) toobtain 36 mg (46%) compound. MS=482.0.

Additional compounds were prepared following the protocol of Scheme 67Step 6, optionally substituting(3-Amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1801 with(3-Amino-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-2021 (prepared per Scheme 67 Steps 1-5, substituting5-chloro-1H-pyrrolo[2,3-b]pyridine 80 with 1H-pyrrolo[2,3-b]pyridine 94in Step 3) and/or 3,5-difluorobenzenesulfonyl chloride 610 with anappropriate sulfonyl chloride. The following compounds were prepared bythis procedure:

-   N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropyl-benzenesulfonamide    (P-1839),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-0913),-   N-[2,4)Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-nitro-benzenesulfonamide    (P-1937),-   N-{4-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-acetamide    (P-1938),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide    (P-1958),-   5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl-phenylsulfamoyl]-furan-2-carboxylic    acid methyl ester (P-1941),-   5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-2-methyl-furan-3-carboxylic    acid methyl ester (P-1942),-   5-Oxazol-5-yl-thiophene-2-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-phenyl]-amide    (P-1943),-   5-Isoxazol-5-yl-thiophene-2-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1948).-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-dimethoxy-benzenesulfonamide    (P-1951),-   2,5-Dimethyl-thiophene-3-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1952),-   2,5-Dimethyl-furan-3-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1953),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-methyl-benzenesulfonamide    (P-1954),-   2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1955),-   2,4-Dimethyl-thiazole-5-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1956),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide    (P-0931),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-5-fluoro-2-methyl-benzenesulfonamide    (P-1961),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-methyl-benzenesulfonamide    (P-1962),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide    (P-1963),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-dimethoxy-benzenesulfonamide    (P-1131),-   2-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-1965),-   3-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide    (P-1966),-   N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-isopropyl,    benzenesulfonamide (P-1968),-   Benzothiazole-6-sulfonic acid    [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide    (P-1969).-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-methoxy-benzenesulfonamide    (P-2011),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide    (P-0885),-   Thiophene-2-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1267),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methyl-benzenesulfonamide    (P-1842),-   N-{4-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl    sulfamoyl]-phenyl}-acetamide (P-1905),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methoxy-benzenesulfonamide    (P-0983),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-trifluoromethyl-benzenesulfonamide    (P-1599),-   5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-furan-2-carboxylic    acid methyl ester (P-1907),-   5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-2-methyl-furan-3-carboxylic    acid methyl ester (P-1908),-   1,2-Dimethyl-1H-imidazole-4-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1911),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide    (P-1912),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-difluoromethoxy-benzenesulfonamide    (P-1916),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-dimethoxy-benzenesulfonamide    (P-191 8),-   2,5-Dimethyl-thiophene-3-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1919),-   2,5-Dimethyl-furan-3-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1920),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-methyl-benzenesulfonamide    (P-1921),-   2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1922),-   2,4-Dimethyl-thiazole-5-sulfonic acid    [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide    (P-1923),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide    (P-1926),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-5-fluoro-2-methyl-benzenesulfonamide    (P-1927),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-methyl-benzenesulfonamide    (P-1928),-   N-[3-(5-Chloro-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-dimethoxy-benzenesulfonamide    (P-1929),-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-cyano-benzenesulfonamide    (P-1931), and-   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-cyano-benzenesulfonamide    (P-1932).    The following table indicates the azaindole (column 2) and the    sulfonyl chloride (column 3) used to afford the target compound    (column 4). The compound number is provided in column 1, with the    observed mass given in column 5.

MS(ESI) Sulfonyl [M + H⁺]⁺ Azaindole chloride Compound observed P-1839

489.9 P-0913

413.9 P-1937

459.1 P-1938

471.1 P-0958

444.3 P-1941

462.3 P-1942

475.9 P-1943

487.1 P-1948

487.1 P-1951

473.9 P-1952

447.9 P-1953

432.3 P-1954

427.9 P-1955

472.3 P-1956

448.7 P-0931

481.9 P-1961

445.9 P-1962

427.9 P-1963

481.1 P-1131

473.9 P-1965

439.1 P-1966

439.1 P-1968

456.3 P-1969

471.1 P-2011

477.9 P-0885

447.9 P-1267

453.9 P-1842

462.3 P-1905

505.1 P-0983

477.9 P-1599

515.9 P-1907

496.3 P-1908

509.9 P-1911

466.3 P-1912

465.9 P-1916

513.9 P-1918

P-1919

481.9 P-1920

465.9 P-1921

461.9 P-1922

505.9 P-1923

483.1 P-1926

483.9 P-1927

479.9 P-1928

461.9 P-1929

507.9 P-1931

473.1 P-1932

473.1

Example 40 Synthesis of4-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylicacid dibutylamide P-1636

Compound P-1636 was synthesized in two steps from 1H-indole-4-carboxylicacid 611 as shown in Scheme 68.

Step 1—Preparation of 1-dibutylcarbamoyl-1H-indole-4-carboxylic acid(612)

To 1H-Indole-4-carboxylic acid (611, 251 mg, 1.56 mmol) intetrahydrofuran (3 mL), was added 2.5M n-butyllithium in hexane (1.28mL, 3.19 mmol) at −78° C. After 30 minutes, dibutyl carbamyl chloride(657 mg, 3.43 mmol) was added and stirred for two hours. The reactionsolution was quenched with 1M HCl (aq.) and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate, filtrated and concentrated. The desired compound wasisolated with silica gel column chromatography using 10% ethyl acetatein hexane to give a white solid (612, 88 mg, 18%). MS (ESI)[M−H⁺]⁺=315.1.

Step 2—Preparation of4-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylicacid dibutylamide (P-1636)

To 1-dibutylcarbamoyl-1H-indole-4-carboxylic acid (612, 78 mg, 0.25mmol) in dichloromethane (2 mL), thionyl chloride (25 μL, 0.34 mmol) wasadded and stirred for one hour, followed by rotary evaporation to removesolvents to provide the dried acid chloride, which was dissolved indichloromethane for later use. Meanwhile,5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 55 mg, 0.28 mmol, preparedas described in Example 17) in dichloromethane (8 mL), was mixed withaluminum trichloride (215 mg, 1.6 mmol) and stirred for one hour,followed by addition of the dried acid chloride in dichloromethane (3mL). The reaction was stirred at room temperature overnight, thenquenched with methanol and all volatiles were removed. The desiredcompound was isolated with silica gel column chromatography using 10%methanol in dichloromethane to give a solid (P-1636, 11 mg, 9%). MS(ESI) [M+H⁺]⁺=494.3.

Additional compounds were prepared following the protocol of Scheme 68,substituting dibutyl carbamyl chloride with a suitable reagent in Step 1and optionally substituting 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89with 5-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (see Example17) in Step 2. The following compounds were prepared following thisprocedure

-   [1-(Butane-1-sulfonyl)-1H-indol-4-yl]-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1661),-   4-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylic    acid pentylamide (P-1702),-   4-(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-indole-1-carboxylic    acid dipropylamide (P-1722), and-   4-[5-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-indole-1-carboxylic    acid butylamide (P-1827).    The following table indicates the reagent used in place of dibutyl    carbamyl chloride (column 2) and the azaindole (column 3) used to    afford the target compound (column 3). The compound number is    provided in column 1, and the observed mass is given in column 5.

MS (ESI) [M + H⁺]⁺ Step 1 reagent Azaindole Compound observed P-1661

459.2 P-1702

452.3 P-1722

466.3 P-1827

468.3

Example 41 Synthesis of3-(3-Benzyloxy-2-chloro-6-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridineP-1852,(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1853 and Related Compounds

Compounds P-1852 and P-1853 were synthesized in four steps from2-chloro-4-fluorophenol 617 and 1H-pyrrolo[2,3-b]pyridine 94 as shown inScheme 69.

Step 1—Preparation of 1-Benzyloxy-2-chloro-4-fluoro-benzene (618)

To a solution of 2-chloro-4-fluorophenol (617, 7 g, 0.05 mol) intetrahydrofuran (100 mL) was added sodium hydride (1.8 g, 95% drypowder, 0.071 mol) at room temperature over 15 minutes under anatmosphere of nitrogen. The reaction mixture was stirred at roomtemperature for 30 minutes. Benzyl bromide (10 g, 0.060 mol) was addedslowly to the reaction mixture, then stirred at room temperatureovernight. The reaction mixture was poured into ice water, extractedwith ethyl acetate, washed with hydrochloric acid (10%), water, brine,and dried over magnesium sulfate. After removal of solvent, the residuewas purified by silica gel column chromatography eluting with ethylacetate in hexane to provide compound as a white solid (618, 7.6 g,60%).

Step 2—Preparation of 3-Benzyloxy-2-chloro-6-fluoro-benzaldehyde (619)

To a solution of 1-benzyloxy-2-chloro-4-fluoro-benzene (618, 5.8 g,0.024 mol) in tetrahydrofuran (100 mL) was added 2.50 M ofn-butyllithium (2.7 mL, 2.50 M in hexane, 0.029 mol) slowly at −78° C.over 15 minutes under nitrogen. The reaction mixture was stirred at −78°C. for 30 minutes. To the reaction mixture was then addedN,N-dimethylformamide (4.2 mL, 0.054 mol). The reaction was allowed towarm to room temperature and was continued at room temperatureovernight. The reaction mixture was poured into ice water, extractedwith ethyl acetate, washed with hydrochloric acid (10%), water, brine,and dried over magnesium sulfate. After removal of solvent, the residuewas purified by silica gel column chromatography eluting with ethylacetate in hexane to provide the compound as a white solid (619, 2.1 g,32%). MS (ESI) [M+H⁺]⁺=265.08.

Step 3—Preparation of 3-[(3-Benzyloxy-2-chloro-6fluoro-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (P-1867) and(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1868)

A mixture of 1H-pyrrolo[2,3-b]pyridine (94, 0.5 g, 4 mmol),3-benzyloxy-2-chloro-6-fluoro-benzaldehyde (619, 1.3 g, 4.9 mmol), andpotassium hydroxide (0.99 g, 18 mmol) in methanol (30 mL) was stirred atroom temperature overnight. The reaction mixture was concentrated andthe residue was dissolved in ethyl acetate and water. The organic layerwas collected and washed with brine. After removal of solvent, theresidue was purified by silica gel column chromatography eluting withethyl acetate in hexane to provide compound P-1867 as a white solid (1.3g, 70%, MS (ESI) [M+H⁺]⁺=397.16), and compound P-1868 as an off-whitesolid (0.2 g, 10, MS (ESI) [M+H⁺]⁺=383.14).

Step 4a—Preparation of3-(3-Benzyloxy-2-chloro-6-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine(P-1852)

A mixture of3-[(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine(P-1867, 0.1 g, 0.2 mmol), trifluoroacetic acid (0.6 mL, 8 mmol), andtriethylsilane (0.3 mL, 2 mmol) in acetonitrile (10 mL) was refluxed for2 hours. The mixture was concentrated and the residue was dissolved inethyl acetate. The solution was washed with saturated sodiumbicarbonate, brine, and dried over sodium sulfate. After removal ofsolvent, the residue was purified by silica gel column chromatographyeluting with methanol in dichloromethane to provide compound as anoff-white solid (P-1852, 62 mg, 70%). MS (ESI) [M+H⁺]⁺=367.16.

Step 4b—Preparation of(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1853)

To a solution of(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(P-1868, 65 mg, 0.17 mmol) in tetrahydrofuran (10 mL) was addedDess-Martin periodinane (79 mg, 0.19 mmol) at 0° C. The reaction mixturewas stirred at room temperature for 2 hours. The reaction was quenchedwith a saturated solution of sodium thiosulfate, extracted with ethylacetate, washed with sodium bicarbonate, brine, and dried over magnesiumsulfate. After removal of solvent, the residue was purified by silicagel column chromatography eluting with methanol in dichloromethane toprovide the compound as a light yellow solid (P-1853, 32 mg, 50%). MS(ESI) [M+H⁺]⁺=381.13.

Additional compounds were prepared following the protocol of Scheme 69,optionally replacing 2-chloro-4-fluorophenol 617 with 2,6-difluorophenolor 2,6-dichlorophenol, optionally replacing benzyl bromide with anappropriate substituted benzyl bromide, and optionally replacing1H-pyrrolo[2,3-b]pyridine 94 with an appropriate substituted1H-pyrrolo[2,3-b]pyridine. Azaindoles were purchased or prepared asdescribed in Examples 9 or 16. The following compounds were madefollowing this procedure:

-   3-[2,6-Dichloro-3-(4-chloro-benzyloxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1768),-   [2,6-Dichloro-3-(4-chloro-benzyloxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)methanone    (P-1769),-   (3-Benzyloxy-2,6-difluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1802),-   3-(3-Benzyloxy-2,6-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine    (P-1803),-   3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine    (P-1804),-   3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine    (P-1824),-   (3-Benzyloxy-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1825),-   3-[(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine    (P-1867),-   (3-Benzyloxy-2-chloro-6-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol    (P-1868),-   [2-Chloro-3-(3-chloro-benzyloxy)-6-fluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1869),-   [2-Chloro-3-(4-chloro-benzyloxy)-6-fluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-1874),-   3-[2,6-Difluoro-3-(pyridin-4-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1993), and-   3-[3-(4-Chloro-2-fluoro-benzyloxy)-2,6-difluoro-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1992).    The phenol, benzyl bromide and azaindole used in Steps 1, 2, and 3,    respectively, are indicated in columns 2, 3, and 4 of the following    table, respectively, to afford the target compound (column 5). The    compound number is provided in column 1, and the observed mass is    given in column 6.

MS (ESI) Benzyl [M + H⁺]⁺ Phenol bromide Azaindole Compound observedP-1768

417.14 P-1769

431.09 P-1802

365.23 P-1803

351.23 P-1804

381.26 P-1824

385.22 P-1825

399.21 P-1869

415.24 P-1874

415.23 P-1993

352.39 P-1992

403.32

Example 42 Synthesis of(3-Benzyloxy-2-methyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1848 and 3-(3-Benzyloxy-2-methyl-benzyl)-1H-pyrrolo[2,3-b]pyridineP-1857

Compounds P-1848 and P-1857 were synthesized in five steps fromcompounds 620 and 1H-pyrrolo[2,3-b]pyridine 94 as shown in Scheme 70.

Step 1 Preparation of 3-Benzyloxy-2-methyl-benzoic acid (621)

To a solution of 3-hydroxy-2-methyl-benzoic acid (620, 5.0 g, 0.033 mol)in tetrahydrofuran (100 mL) and N,N-dimethylformamide (50 mL), sodiumhydride (4.4 g as 60% dispersion in mineral oil, 0.11 mol) was addedslowly over 30 minutes and the reaction was stirred at 0° C. under anatmosphere of nitrogen. The reaction mixture was allowed to warm to roomtemperature, then stirred at room temperature for 1 hour. Benzyl bromide(9.0 mL, 0.076 mol) was added slowly into the reaction mixture, and thereaction mixture was stirred at room temperature overnight. The reactionmixture was poured into water, extracted with ethyl acetate, washed witha solution of ammonium chloride and ammonium hydroxide (4:1), brine, anddried over magnesium sulfate. After removal of solvent, the residue waspurified by silica gel column chromatography eluting with ethyl acetatein hexane to provide the compound as a white solid (621, 5.8 g, 73%).

Step 2—Preparation of (3-Benzyloxy-2-methyl-phenyl)-methanol (622)

To a solution of 3-benzyloxy-2-methyl-benzoic acid (621, 3.0 g, 0.012mol) in tetrahydrofuran (100 mL), lithium aluminum hydride (25 mL, 1Msolution in tetrahydrofuran, 0.025 mol) was added dropwise at 0° C. for5 minutes. The reaction mixture was then stirred at room temperatureovernight under an atmosphere of nitrogen. After sodium sulfatedecahydrate (20.0 g, 0.062 mol) was added, the reaction mixture wasstirred at room temperature for 10 minutes. A white solid was collectedby filtration. The solid compound was further washed with a mixture ofhexane and dichloromethane (9:1) and dried under high-vacuum (622, 2.8g, 91%).

Step 3—Preparation of 3-Benzyloxy-2-methyl-benzaldehyde (623)

To a solution of (3-benzyloxy-2-methyl-phenyl)-methanol (622, 627 mg,2.75 mmol) in tetrahydrofuran (60 mL) was added Dess-Martin periodinane(2.9 g, 6.87 mmol) at 0° C. The resulting mixture was stirred at 0° C.for 50 minutes. The reaction mixture was quenched with a solution ofsaturated sodium thiosulfate, extracted with ethyl acetate, washed withsodium bicarbonate, brine, and dried over magnesium sulfate. Afterremoval of solvent, the residue was purified by silica gel columnchromatography eluting with ethyl acetate in hexane to provide thecompound as a white solid (623, 0.55 g, 84%).

Step 4—Preparation of(3-Benzyloxy-2-methyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(624) and3-[(3-Benzyloxy-2-methyl-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine(625)

A mixture of 1H-pyrrolo[2,3-b]pyridine (94, 0.33 g, 2.8 mmol),3-benzyloxy-2-methyl-benzaldehyde (623, 0.55 g, 2.4 mmol), and potassiumhydroxide (0.39 g, 6.1 mmol) in methanol (40 mL) was stirred at roomtemperature for 17 hours. The reaction mixture was poured into water andthen extracted with ethyl acetate. The organic layer was collected,washed with brine, and dried over sodium sulfate. After removal ofsolvent, the residue was purified by silica gel column chromatographyeluting with ethyl acetate in hexane to provide compound 624 as anoff-white solid (330 mg, 39%, MS (ESI) [M+H⁺]⁺=345.29, and compound 625as a white solid (24 mg, 3%, MS (ESI) [M+H⁺]⁺=359.30).

Step 5a—Preparation of(3-Benzoxy-2-methyl-phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1848)

To a solution of(3-Benzyloxy-2-methyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(624, 0.12 g, 0.35 mmol) in tetrahydrofuran (15 mL) was addedDess-Martin periodinane (0.37 g, 0.89 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 50 minutes, then quenched with asaturated solution of sodium thiosulfate, extracted with ethyl acetate,washed with sodium bicarbonate, brine, and dried over magnesium sulfate.After removal of solvent, the residue was washed with a mixture of ethylether and hexanes (1:1) to provide the compound as a yellow solid(P-1848, 108 mg, 90%). MS (ESI) [M+H⁺]⁺=343.22.

Step 5b—Preparation of3-(3-Benzyloxy-2-methyl-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1857)

A mixture of3-[(3-benzyloxy-2-methyl-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine(625, 24 mg, 0.067 mmol), trifluoroacetic acid (1 mL, 13 mmol), andtriethylsilane (2 mL, 12.5 mmol) in acetonitrile (10 mL) was refluxedfor 4 hours. The mixture was concentrated and the residue was dissolvedin ethyl acetate. The solution was washed with saturated sodiumbicarbonate, brine, and dried over sodium sulfate. After removal ofsolvent, the residue was washed with a mixture of ethyl ether andhexanes (1:1) to provide the compound as a yellow solid (P-1857, 17 mg,75%). MS (ESI) [M+H⁺]⁺=329.24.

Example 43 Synthesis of[3-(4-chloro-benzyloxy)-2-ethoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1892 and3-[3-(4-chloro-benzyloxy)-2-ethoxy-benzyl]-1H-pyrrolo[2,3-b]pyridineP-1893

Compounds P-1892 and P-1893 were synthesized in five steps fromcompounds 626, 557 and 1H-pyrrolo[2,3-b]pyridine 94 as shown in Scheme71.

Step 1—Preparation of 2,3-Bis-(4-chloro-benzyloxy)-benzaldehyde (627)

To a solution of 2,3-dihydroxybenzaldehyde (626, 2.0 g, 14.5 mmol) intetrahydrofuran (100 mL) was added sodium hydride (0.52 g, 13.0 mmol) at0° C. under an atmosphere of nitrogen. The reaction mixture was allowedto warm to room temperature and was stirred at room temperature for 30minutes. To the reaction mixture was then added 4-chlorobenzyl bromide(557, 2.7 g, 13.0 mmol). The reaction mixture was stirred at roomtemperature under an atmosphere of nitrogen overnight.N,N-dimethylformamide (50 mL) was added into the reaction mixture and itwas stirred at room temperature for 24 hours. The reaction mixture waspoured into ice water and extracted with ethyl acetate. The organiclayer was collected, washed with brine, and dried over magnesiumsulfate. After removal of solvent, the residue was purified by silicagel column chromatography eluting with ethyl acetate in hexane toprovide the compound as an off-white solid (627, 2.3 gm, 46%).

Step 2—Preparation of 3-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde(628)

To magnesium (0.098 g, turnings, 4.0 mmol) in a mixture of anhydrousether (20 mL) and benzene (20 mL) at 0° C., bromine (0.10 mL, 2.0 mmol)was added dropwise. When the reaction had started, stirring wascommenced and the addition of bromine continued until complete. The icebath was removed and the reaction mixture was heated until the solutionwas almost colorless. After cooling down, the reaction mixture wasslowly added to a solution of 2,3-bis-(4-chloro-benzyloxy)-benzaldehyde(627, 0.78 g, 2.0 mmol) in benzene (60 mL) at room temperature whilestirring vigorously. Upon completion of the addition, the reactionmixture was stirred at room temperature overnight, then refluxed for 36hours. After the reaction mixture was cooled down to room temperature, asolid was collected by filtration and washed with benzene, then boiledin hydrochloric acid (100 mL, 1.0 M) for 30 minutes. After cool down,the solution was extracted with dichloromethane. The organic layer waswashed with brine and dried over magnesium sulfate. An off-white solidwas obtained after removal of the solvent (628, 0.32 mg, 60%). MS (ESI)[M−H−]=261.25.

Step 3—Preparation of 3-(4-chloro-benzyloxy)-2-ethoxy-benzaldehyde (629)

To a mixture of 3-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde (110 mg,0.42 mmol), potassium carbonate (150 mg, 1.1 mmol) in acetonitrile (8mL) was added iodoethane (0.2 mL, 2.5 mmol) at room temperature. Themixture was stirred at 98° C. for 18 hours. The reaction mixture waspoured into a solution of saturated ammonium chloride and was extractedwith ethyl acetate. The organic layer was collected, washed with brine,and dried over magnesium sulfate. After removal of solvent, a lightyellow solid was obtained (629, 116 mg, 95%).

Step 4—Preparation of[3-(4-chloro-benzyloxy)-2-ethoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(630) and3-{3-(4-chloro-benzyloxyl)-2-methoxy-phenyl-methoxy-methyl}-1H-pyrrolo[2,3-b]pyridine(631)

A mixture of 1H-Pyrrolo[2,3-b]pyridine (94, 26 mg, 0.22 mmol),3-(4-chloro-benzyloxy)-2-ethoxy-benzaldehyde (629, 54 mg, 0.19 mmol),and potassium hydroxide (30 mg, 0.4.6 mmol) in methanol (5 mL) wasstirred at room temperature for 4 days. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer wascollected, washed with brine, and dried over sodium sulfate. Afterremoval of solvent, the residue was purified by silica gel columnchromatography eluting with ethyl acetate in hexane to provide compound630 as an off-white solid (20 mg, 26%, MS (ESI) [M+H⁺]⁺=409.32) andcompound 631 as an off-white solid (44 mg, 56%, MS (ESI) [M+H⁺]⁺=423.33.

Step 5a—Preparation of[3-(4-chloro-benzyloxy)-2-ethoxy-phenyl]-(H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1892)

To a solution of[3-(4-chloro-benzyloxy)-2-ethoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(630, 20 mg, 0.05 mmol) in tetrahydrofuran (8 mL) was added Dess-Martinperiodinane (52 mg, 0.12 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 50 minutes. The reaction was quenched with a saturatedsolution of sodium thiosulfate, extracted with ethyl acetate, washedwith sodium bicarbonate, brine, and dried over magnesium sulfate. Afterremoval of solvent, the residue was washed with a mixture of ethyl etherand hexanes (1:1) to provide the compound as a yellow solid (P-1892, 15mg, 75%). MS (ESI) [M+H⁺]⁺=407.38.

Step 5b—Preparation of3-[3-(4-chloro-benzyloxy)-2-ethoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine(P-1893)

A mixture of3-{[3-(4-chloro-benzyloxy)-2-ethoxy-phenyl]-methoxy-methyl}-1H-pyrrolo[2,3-b]pyridine(631, 44 mg, 0.1 mmol), trifluoroacetic acid (1 mL, 13 mmol), andtriethylsilane (2 mL, 12.5 mmol) in acetonitrile (10 mL) was refluxedfor 4 hours. The mixture was concentrated and the residue was dissolvedin ethyl acetate. The solution was washed with saturated sodiumbicarbonate, brine, and dried over sodium sulfate. After removal ofsolvent, the residue was washed with a mixture of ethyl ether andhexanes (1:1) to provide the compound as a yellow solid (P-1893, 40 mg,98%). MS (ESI) [M+H⁺]⁺=393.39.

[3-(4-Chloro-benzyloxy)-2-methoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1891),[3-(4-Chloro-benzyloxy)-2-(2,2,2-trifluoroethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-2076), and[3-(4-chloro-2-fluoro-benzyloxy)-2-ethoxy-phenyl]-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-2016)

were prepared following the protocol of Scheme 71, substitutingiodoethane with iodomethane in Step 3 to provide P-1891, or substitutingiodoethane with 2-iodo-1,1,1-trifluoroethane in Step 3 to provideP-2076, or substituting 4-chlorobenzyl bromide 557 with4-chloro-2-fluoro-benzyl bromide in Step 1 and 7-azaindole 94 with5-methoxy-7-azaindole in Step 4 to provide P-2016. MS (ESI)[M+H⁺]⁺=393.4 (P-1891), 461.08 (P-2076), and 455.2 (P-2016).

Example 44 Synthesis of Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amideP-0956

Compound P-0956 was synthesized in three steps from5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine 514 and propane-1-sulfonicacid (2,4-difluoro-3-formyl-phenyl)-amide 73 as shown in Scheme 72.

Step 1-Preparation of Propane-1-sulfonic acid(3-{[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-hydroxy-methyl}-2,4-difluoro-phenyl)-amide(632) and Propane-1-sulfonic acid(3-{[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methoxy-methyl}-2,4-difluoro-phenyl)-amide(633)

To a suspension of 5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine (514,64.9 g, 158 mM, prepared as described in Example 17) andpropane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (73, 90.4g, 191 mM, prepared as described in Example 7) in methanol in a waterbath was added potassium hydroxide (128.8 g, 1.28 M). The reaction wasstirred 72 hours at room temperature and then adjusted to pH 7 with 4Nhydrochloric acid. The resulting mixture was evaporated in vacuo toremove methanol and extracted 3× with ethyl acetate. The combinedorganic layers were dried over sodium sulfate and evaporated in vacuo togive a crude oil. The crude oil was triturated with 3:1 MTBE/heptane togive a 1:3 solid mixture of 632 and 633 that was used directly for thenext step.

Step 2—Preparation of Propane-1-sulfonic acid(3-{[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-hydroxy-methyl}-2,4-difluoro-phenyl)-amide(632)

To a solution of 632 and 633 (ca. 315 mM) in acetic acid was added 48%hydrobromic acid (final 8%). The resulting mixture was stirred overnightat room temperature and then evaporated in vacuo. The crude residue wastaken up with equal volumes of ethyl acetate and water, and adjusted topH 7 with solid potassium carbonate. The layers were split and theaqueous layer was extracted 2× with ethyl acetate. The combined organiclayers were dried over sodium sulfate and evaporated in vacuo to give632 as a viscous oil that was used directly for the next step.

Step 3—Preparation of Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(P-0956)

To a solution of 632 (ca. 386 mM) in 1,4-dioxane was added2,3-dichloro-5,6-dicyanobenzoquinone (83.8 g, 502 mM) followed by water(final 4.8%). The resulting mixture was stirred 2 hours at roomtemperature and then quenched with one volume of saturated sodiumbicarbonate. The mixture was evaporated in vacuo to remove 1,4-dioxaneand extracted 3× with ethyl acetate. The combined organic layers weredried over sodium sulfate and evaporated in vacuo to give a crude solidthat was purified on a silica-gel column with 94:5:1dichloromethane/methanol/ammonium hydroxide as eluent to give P-0956(approximately 50% yield for 3 steps) as a white solid.

Example 45 Synthesis of3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 635

3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 635 wassynthesized in one step from 3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 asshown in Scheme 73.

Step 1—Preparation of3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635)

3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 (2.00 g, 8.20 mmol) was dissolvedin N,N-dimethylformamide (50 mL). Sodium hydride (60% dispersion inmineral oil, 390 mg, 9.8 mmol) was added. After 20 minutes,triisopropylsilyl chloride (1.74 mL, 8.20 mmol) was added dropwise.After 1.5 hours, the reaction was poured into water and extracted withethyl acetate, washed with saturated sodium bicarbonate and brine. Theorganic portions were dried over anhydrous sodium sulfate andconcentrated. Purification by silica gel chromatography, 0-25% gradientethyl acetate/hexane gave compound 635 as a white solid (3.224 g,98.2%). ¹H-NMR was consistent with the desired compound.

Example 46 Synthesis of1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine 636

1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine 636 wassynthesized in one step from 3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 asshown in Scheme 74.

Step 1—Preparation of1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (636)

3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 (1.11 g, 4.6 mmol) was dissolved intetrahydrofuran (120 mL). Sodium hydride (60% dispersion in mineral oil,0.13 g, 5.5 mmol) was added, followed by tert-butyldimethylsilylchloride (0.85 g, 5.5 mmol). The reaction was stirred at roomtemperature overnight. The reaction was poured into water and extractedwith ethyl acetate. The organic portion was washed with brine, driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified with silica gel column chromatography elutingwith 30% ethyl acetate in hexane to give the compound as a white solid(636, 100 mg, 15%).

Example 47 Synthesis of[5-(4-chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-2024

[5-(4-Chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-(1-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-2024 was synthesized in six steps from Kojic acid, 3, and3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 2, as shown inScheme 75.

Step 1—Preparation of 5-(4-chloro-benzyloxy)-2-hydroxymethyl-pyran-4-one(638)

Kojic acid (637, 5.00 g, 35.2 mmol) and 4-chlorobenzyl bromide (557,7.95 g, 38.7 mmol) were suspended in methanol (40 mL) in an 80 mL scaledtube. Sodium hydroxide in water (12 M, 2.93 mL) was added. The reactionwas heated at 80° C. overnight. The resulting suspension wasconcentrated. Water was added and the mixture was filtered and washedwith water to provide a brown solid. Washing with minimal methanol onthe filter removed the brown color. A white solid (638, 7.58 g, 80%) wasisolated. ¹H-NMR was consistent with the desired compound.

Step 2—Preparation of5-(4-chloro-benzyloxy)-2-hydroxymethyl-1H-pyridin-4-one (639)

5-(4-Chloro-benzyloxy)-2-hydroxymethyl-pyran-4-one (638, 8.00 g, 3.00mmol) was suspended in ammonium hydroxide (200 mL) in an 80 mL sealedtube. The reaction was heated at 90° C. overnight. Upon cooling, thereaction was lowered to pH 10 with 6N HCl to provide a beige solid thatwas collected by filtration (639, 7.8 g, 98%).

Step 3—Preparation of[5-(4-chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanol (640)

5-(4-Chloro-benzyloxy)-2-hydroxymethyl-1H-pyridin-4-one (639, 1.06 g,3.99 mmol) was dissolved in methanol (8.5 mL) and N,N-dimethylformamide(46 mL). Trimethylsilyldiazomethane in hexane (2.00 M, 3.99 mL) wasadded. The reaction was stirred at room temperature overnight, thenadditional trimethylsilyldiazomethane in hexane (2.00 M, 3.99 mL) wasadded. The reaction was stirred at room temperature for 2 days. Themixture was adsorbed onto silica and purified by silica gelchromatography, methanol:dichloromethane to provide the compound (640,798 mg, 72%).

MS (ESI) [M+H⁺]⁺=280.4, 282.4.

Step 4—Preparation of5-(4-chloro-benzyloxy)-4-methoxy-pyridine-2-carbaldehyde (641)

[5-(4-Chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanol (640, 480 mg,1.7 mmol) was dissolved in dimethyl sulfoxide (26 mL) and Dess-Martinperiodinane (909 mg, 2.1 mmol) was added. The reaction was allowed tostir at room temperature for 2 hours. The reaction was concentratedunder high vacuum and then poured into a solution of NaHCO₃ and Na₂S₂O₃.The mixture was extracted with ethyl acetate. The organic portions weredried with anhydrous sodium sulfate and filtered. The filtrate wasadsorbed onto silica and purified by silica gel chromatography, ethylacetate:hexanes, to provide the desired compound as a white powder (641,343 mg, 72%).

Step 5—Preparation of[5-(4-chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(642)

3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 180 mg,0.450 mmol) was dissolved in tetrahydrofuran (2.5 mL) and the reactionwas cooled to −20° C. under an atmosphere of nitrogen.Isopropylmagnesium chloride in tetrahydrofuran (2.00 M, 0.243 mL) wasadded. The reaction was stirred for 1 hour, during which the temperaturerose to 0° C. The reaction was cooled to −20° C. and5-(4-chloro-benzyloxy)-4-methoxy-pyridine-2-carbaldehyde (641, 80.0 mg,0.288 mmol) in tetrahydrofuran (0.75 mL) was added. The reaction wasallowed to warm to room temperature and stirred overnight. The reactionwas quenched with methanol and adsorbed onto silica, then purified bysilica gel chromatography, methanol: dichloromethane, to provide thedesired product, (642, 94 mg, 59%). ¹H-NMR was consistent with thedesired compound. MS (ESI) [M+H⁺]⁺=552.4, 554.4, 555.4.

Step 6—Preparation of[5-(4-chloro-benzyloxy-4-methoxy-pyridin-2-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-2024)

[5-(4-Chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(642, 60.0 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2.00 mL).Dess-Martin periodinane (55.3 mg, 0.13 mmol) was added to the reactionand it was stirred at room temperature overnight. The mixture wasextracted with ethyl acetate and saturated sodium bicarbonate. Theorganic portions were dried with anhydrous sodium sulfate, filtered andthe filtrate was adsorbed onto silica and purified by silica gelchromatography, methanol:dichloromethane, to provide the desiredcompound (P-2024, 10.7 mg, 25%). ¹H-NMR was consistent with the desiredcompound. MS (ESI) [M+H⁺]⁺=394.1, 396.1.

Example 48 Synthesis of3-4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-benzyl-1H-pyrrolo[2,3-b]pyridineP-2000

3-4-[1-(4-Chloro-phenyl)-ethoxy]-3-methoxy-benzyl-1H-pyrrolo[2,3-b]pyridineP-2000 was synthesized in three steps from vanillin 105,4-chlorophenylmethylcarbinol 643, and1-(tert-butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine 636, asshown in Scheme 76.

Step 1—Preparation of4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-benzaldehyde (644)

4-Chlorophenylmethylcarbinol (643, 0.668 mL, 6.57 mmol) was dissolved intetrahydrofuran (60.0 mL) at 0° C. under an atmosphere of nitrogen.4-Hydroxy-3-methoxybenzaldehyde (105, 1.00 g, 6.57 mmol) andtriphenylphosphine (2.07 g, 7.89 mmol) were added to the reaction,followed by diisopropyl azodicarboxylate (1.55 mL, 7.89 mmol) over 10minutes. The reaction was stirred for 2 hours. The mixture was adsorbedonto silica and purified by silica gel chromatography, ethylacetate:hexanes, to provide the desired compound, (644, 1.14 g, 60%).¹H-NMR was consistent with the desired compound.

Step 2—Preparation of[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-phenyl-methanol(645)

1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (636,647.0 mg, 1.81 mmol) was dissolved in tetrahydrofuran (10.0 mL) at −20°C. under an atmosphere of nitrogen. Isopropylmagnesium chloride intetrahydrofuran (2.0 M, 0.98 mL) was added to the reaction. The reactionwas stirred for 1 hour, during which the temperature rose to 0° C. Thereaction was cooled to −20° C. and4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-benzaldehyde (644, 420 mg, 1.4mmol) in tetrahydrofuran (3.00 mL) was added. The reaction was stirredfor 2 hours during which time the temperature rose to 10° C. Thereaction was quenched with methanol and adsorbed onto silica, thenpurified by silica gel chromatography, ethyl acetate:hexanes, to providethe desired compound, (645, 463 mg, 61%). ¹H-NMR was consistent with thedesired compound.

Step 2—Preparation of3-4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-benzyl-1H-pyrrolo[2,3-b]pyridine(P-2000)

[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-phenyl-methanol(645, 0.200 g, 0.382 mmol) was dissolved in acetonitrile (5.00 mL).Trifluoroacetic acid (0.138 mL) was added and the reaction was stirredfor five minutes. Triethylsilane (0.285 mL) was added and the reactionwas heated at 80° C. for 2 hours. The reaction was concentrated, thenredissolved in ethyl acetate and adsorbed onto silica and purified bysilica gel chromatography, ethyl acetate:hexanes, to provide the desiredcompound (P-2000, 57 mg, 38%). ¹H-NMR was consistent with the desiredcompound. MS (ESI): [M+H⁺]⁺=393.3, 395.3.

Example 49 Synthesis of5-[4-(2-methoxyethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine 648

5-[4-(2-Methoxyethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine 648 wassynthesized in two steps from 4-bromophenol 646 as shown in Scheme 77.

Step 1—Preparation 1-Bromo-4-(2-methoxy-ethoxy)-benzene (647)

To a solution of 4-bromophenol (646, 5.0 g, 28.9 mmol) indimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8mmol) and 1-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under anatmosphere of nitrogen. The reaction mixture was stirred at ambienttemperature overnight and concentrated under reduced pressure. Theresidue was slurried in ethyl acetate (50 mL) and filtered. The filtratewas washed with saturated sodium bicarbonate solution, dried overmagnesium sulfate and filtered. Silica gel column chromatography (0-10%ethyl acetate in hexanes) gave the desired compound as a colorless oil(647, 3.2 g, 48%).

Step 2—Preparation of5-[4-(2-Methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine (648)

To a solution of5-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(1.1 g, 4.3 mmol) in tetrahydrofuran (40 mL) was added1-bromo-4-(2-methoxy-ethoxy)-benzene (647, 1.50 g, 6.49 mmol) andtetrakis(triphenylphosphine)palladium (0) (0.25 g, 0.21 mmol). Thereaction mixture was stirred with potassium carbonate solution (10 mL,1.0 M) and warmed to reflux overnight. The biphasic reaction mixture wasdiluted with ethyl acetate (50 mL) and saturated sodium carbonatesolution (20 mL). The organic layer was separated, washed with brine,dried over magnesium sulfate and purified by silica gel columnchromatography (50-100% ethyl acetate in hexanes) to give the desiredcompound as a colorless solid (648, 782 mg, 67%). MS (ESI)[M+H⁺]⁺=267.4.

Example 50 Synthesis of3-[2-fluoro-5-methoxy-4-(pyridin-4-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridineP-2040 and Related Compounds

Compound P-2040 was synthesized in one step from5-fluoro-2-methoxy-4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol649 and pyridin-4-yl-methanol 650 as shown in Scheme 78.

Step 1—Preparation of3-[2-fluoro-5-methoxy-4-(pyridin-4-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine(P-2040)

5-Fluoro-2-methoxy-4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl)-phenol(649, 10 mg, 0.024 mmol, prepared as described in Example 52) wascombined with pyridin-4-yl-methanol (650, 3.2 mg, 0.029 mmol) in a 4 mLvial and dissolved in dry tetrahydrofuran (200 μl). Triphenylphosphine(7.7 mg) was added and the solution was shaken until homogenous. Themixture was cooled to below 0° C. in a liquid nitrogen bath anddiisopropyl azodicarboxylate solution (50 μl of 20 mg/50 μl in THF) wasadded. The reaction mixture was allowed to warm to room temperature.After 2 hours, the solvent was removed under reduced atmosphere. Thecrude material was dissolved in dimethyl sulfoxide (300 μl) andpotassium fluoride (10 mg, 0.18 mmol) was added. The mixture was heatedgently and allowed to react overnight at room temperature. The vial wascentrifuged and the DMSO solution was purified by reverse phase HPLCusing a YMC-Pack ODS-A C-18 column (50 mm×10 nm ID), and eluting withwater with 0.1% TFA and a gradient of 15%-80% acetonitrile with 0.1% TFAover 8 minutes and a flow rate of 6 mL/minute to provide the compound(P-2040, 4.4 mg, 50%). MS (ESI) [M+H⁺]⁺=364.3.

Additional compounds were prepared following the protocol of Scheme 78,replacing pyridin-4-yl-methanol 650 with an appropriate alcohol. Thefollowing compounds were made following this procedure:

-   3-[2-Fluoro-5-methoxy-4-(2-morpholin-4-yl-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2037),-   3-[2-Fluoro-5-methoxy-4-(pyridin-3-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2038),-   3-[2-Fluoro-5-methoxy-4-(6-methyl-pyridin-2-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2039),-   3-[2-Fluoro-5-methoxy-4-(pyridin-2-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2041),-   3-[2-Fluoro-4-(2-fluoro-4-trifluoromethyl-benzyloxy)-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2042),-   3-[4-(4-Chloro-2-fluoro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-1973),-   3-[4-(2,4-Dimethyl-thiazol-5-ylmethoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2043),-   3-[4-(2,5-Dimethyl-2,1-pyrazol-3-ylmethoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2044),-   3-[2-Fluoro-5-methoxy-4-(3-morpholin-4-yl-propoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2045),-   1-{2-[5-Fluoro-2-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-ethyl}-pyrrolidin-2-one    (P-2046),-   3-[2-Fluoro-4-(2-fluoro-benzyloxy)-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2047),-   3-[2-Fluoro-5-methoxy-4-(3-methyl-pyridin-4-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2048),-   3-[2-Fluoro-5-methoxy-4-(6-trifluoromethyl-pyridin-3-ylmethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2049),-   3-[4-(2,4-Dichloro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2050),-   3-[2-Fluoro-4-(4-imidazol-1H-yl-benzyloxy)-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2051),-   3-[4-(2,4-Difluoro-benzyloxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2052),-   3-{2-Fluoro-4-[1-(2-fluoro-phenyl)-ethoxy]-5-methoxy-benzyl}-1H-pyrrolo[2,3-b]pyridine    (P-2053),-   3-[4-(3-Cyclopentyl-propoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2054),-   3-[4-(1,5-Dimethyl-1H-pyrazol-3-ylmethoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2055), and-   3-[4-(2-Cyclopentyl-ethoxy)-2-fluoro-5-methoxy-benzyl]-1H-pyrrolo[2,3-b]pyridine    (P-2056)    The following table indicates the alcohol (column 2) used in Scheme    78 to provide the compounds (column 4). Column 1 provides the    compound number and column 4 the observed mass.

MS (ESI) [M + H⁺]⁺ Alcohol Compound observed P-2037

386.3 P-2038

364.3 P-2039

378.3 P-2041

364.3 P-2042

448.7 P-1973

415.1 P-2043

397.9 P-2044

381.1 P-2045

400.3 P-2046

384.3 P-2047

381.1 P-2048

378.3 P-2049

432.3 P-2050

431.1 P-2051

429.1 P-2052

399.1 P-2053

395.1 P-2054

383.1 P-2055

381.1 P-2056

369.1

Example 51 Synthesis of[2,6-difluoro-3-(pyridin-3-ylmethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-2058 and Related Compounds

Compound P-2058 was synthesized in 1 step from(2,6-Difluoro-3-hydroxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone651 and Pyridin-3-yl-methanol 652 as shown in Scheme 79.

Step 1—Preparation of[2,6-Difluoro-3-(pyridin-3-ylmethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-2058)

In a 4 mL vial,(2,6-Difluoro-3-hydroxy-phenyl)-(1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone(651, 10 mg, 0.037 mmol, prepared as described in Example 23) wascombined with pyridin-3-yl-methanol (652, 4.9 mg 0.044 mmol). The solidswere dissolved in dry tetrahydrofuran (200 μl) and triphenylphosphine(11.5 mg, 0.044 mmol) was added. Once the solution was homogenous, themixture was cooled to below 0° C. in liquid nitrogen bath anddiisopropyl azodicarboxylate solution (50 μl of 20 mg/50 μl THF) wasadded. The reaction mixture was allowed to warm to room temperature andthe reaction was continued for 2 hours. The solvents were removed underreduced atmosphere. The resultant residue was diluted with 200 μl DMSOand the mixture purified by reverse phase HPLC using a YMC-Pack ODS-AC-18 column (50 mm×10 mm ID), and eluting with water with 0.1% TFA and agradient of 15%-80% acetonitrile with 0.1% TFA over 8 minutes and a flowrate of 6 mL/minute to provide P-2058 (5.9 mg, 44%). MS (ESI)[M+H⁺]⁺=365.9.

Additional compounds were prepared following the protocol of Scheme 79,replacing pyridin-3-yl-methanol 652 with an appropriate alcohol. Thefollowing compounds were made following this procedure:

-   [2,6-Difluoro-3-(1-methyl-1H-imidazol-2-ylmethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2033),-   [2,6-Difluoro-3-(6-morpholin-4-yl-pyridin-3-ylmethoxy)-phenyl]-(H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2034),-   {2,6-Difluoro-3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-phenyl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2035),-   [3-(6-Diethylamino-pyridin-3-ylmethoxy)-2,6-difluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2036),-   [3-(2-Chloro-4-fluoro-benzyloxy)-2,6-difluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2057),-   [2,6-Difluoro-3-(6-methyl-pyridin-2-ylmethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2059),-   [2,6-Difluoro-3-(pyridin-4-ylmethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2060),-   [3-(4-Chloro-2-fluoro-benzyloxy)-2,6-difluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2061),-   [3-(2,4-Dimethyl-thiazol-5-ylmethoxy)-2,6-difluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2062),-   [3-(2,5-Dimethyl-2H-pyrazol-3-ylmethoxy)-2,6-difluoro-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2063), and-   [2,6-Difluoro-3-(3-morpholin-4-yl-propoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-2064).    The following table indicates the alcohol (column 2) used to afford    the compound (column 3). Column 1 provides the compound number and    column 4 the observed mass.

MS (ESI) [M + H⁺]⁺ Alcohol Compound observed P-2033

369.1 P-2034

451.1 P-2035

447.1 P-2036

437.1 P-2057

417.1 P-2059

380.3 P-2060

365.9 P-2061

417.1 P-2062

399.9 P-2063

383.1 P-2064

402.3

Example 52 Synthesis of5-fluoro-2-methoxy-4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol649

5-Fluoro-2-methoxy-4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol649 was synthesized in five steps from2-fluoro-4-hydroxy-5-methoxy-benzaldehyde 653 and benzyl bromide asshown in Scheme 80.

Step 1—Preparation of 4-Benzyloxy-2-fluoro-5-methoxy-benzaldehyde (654)

2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (653, 1.62 g, 9.52 mmol) wasdissolved in N,N-dimethylformamide (50 mL) and sodium hydride (60%dispersion in mineral oil, 530 mg, 13 mmol) was added. After 20 minutes,benzyl bromide (1.5 mL, 12 mmol) was added to the reaction mixture. Thereaction was stirred at room temperature under an atmosphere of nitrogenfor 5.5 hours. The reaction was poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 0-50% ethyl acetate inhexane to provide compound as a white solid, consistent with the desiredstructure by ¹H-NMR (654, 2.0 g, 81%).

Step 2—Preparation of4-Benzyloxy-2-fluoro-5-methoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(655)

3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 620 mg, 1.5mmol, prepared as described in Example 45) was dissolved intetrahydrofuran (15 mL) at −20° C. under an atmosphere of nitrogen.Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 840 μL) was addedto the reaction. The reaction was stirred for 1.5 hours, during whichthe temperature rose to 5° C. The reaction was cooled to −20° C.4-Benzyloxy-2-fluoro-5-methoxy-benzaldehyde (654, 250 mg, 0.9606 mmol)in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction wasstirred for 2.5 hours during which time the temperature rose to 5° C.The reaction was poured into water. The mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 2-25% ethyl acetate in hexane toprovide compound as a white solid (655, 501 mg, 63%). MS (ESI)[M+H⁺]⁺=535.4.

Step 3—Preparation of3-4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine (656)

(4-Benzyloxy-2-fluoro-5-methoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(655, 1.49 g, 2.79 mmol) was dissolved in acetonitrile (50 mL) andtrifluoroacetic Acid (1.1 mL) was added. The reaction was stirred for 5minutes. Triethylsilane (2.2 mL) was added to the reaction. The reactionwas heated at 80° C. for 6 hours. The reaction was concentrated and thecrude material was dissolved into ethyl acetate and washed with 1 N HCl,saturated sodium bicarbonate, and brine. The organic portion was driedover anhydrous sodium sulfate and concentrated. The solid obtained wasused in the next reaction without further purification (656, 833 mg,83%). MS (ESI) [M+H⁺]⁺=363.4.

Step 4—Preparation of3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(657)

3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine(656, 0.877 g, 2.42 mmol) was dissolved in N,N-dimethylformamide (30mL). Sodium hydride (60% dispersion in mineral oil, 140 mg, 3.6 mmol)was added at room temperature. After 20 minutes, triisopropylsilylchloride (513 μL, 2.42 mmol) was added dropwise. The reaction wasstirred for four hours. The reaction was poured into water and extractedwith ethyl acetate. The organic portion was washed with saturated sodiumbicarbonate and brine. The organic portion was dried over anhydroussodium sulfate and filtered. The filtrate was adsorbed onto silica geland purified by silica gel chromatography using 20-80% ethylacetate/hexane. The resulting material was purified a second time with5-30% gradient ethyl acetate/hexane to provide the desired compound(657, 831 mg, 66%). MS (ESI) [M+H⁺]⁺=519.4.

Step 5-reparation of5-Fluoro-2-methoxy-4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol(649)

3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(657, 0.831 g, 1.60 mmol) was dissolved in methanol (40 mL) andtetrahydrofuran (40 mL). 10% Palladium on carbon (3.41 g) was added. Thereaction was shaken at 50 psi for 1 hour. The reaction was filteredthrough Celite and washed with methanol. The organic portion was passedthrough celite several times until a clear solution was obtained. Theorganic portion was concentrated under reduced pressure to provide thedesired compound as an off-white solid (649, 587 mg, 86%). MS (ESI)[M+H⁺]⁺=429.5.

Example 53 Synthesis of(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-hydroxy-phenyl)-methanoneP-0067 and Related Compounds

Compound P-0067 was synthesized in two steps from5-bromo-1H-pyrrolo[2,3-b]pyridine 67 as shown in Scheme 10.

Step 1—Preparation of(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl-methanone(P-0265)

To 5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 2.00 g, 0.0102 mol) inmethylene chloride (120 mL), under an atmosphere of nitrogen, was addedaluminum trichloride (8.20 g, 0.0615 mol). The reaction was stirred atroom temperature for 60 minutes, then 2-fluoro-3-methoxy-benzoylchloride (34, 2.12 g, 0.0112 mol, prepared from the correspondingcarboxylic acid using the protocol of Example 1, Scheme 13, Step 4),dissolved in methylene chloride (20.0 mL), was added. After 2 hours, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,concentrated and purified by silica gel chromatography, eluting with 25%ethyl acetate in hexane to provide P-0265 (approx 2.6 g, 73%). MS (ESI)[M−H⁺]⁺=347, 349.

Step 2—Preparation of(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl-(2-fluoro-3-hydroxy-phenyl)-methanone(P-0067)

To(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl)-methanone(P-0265, 430.0 mg, 1.23 mmol) in methylene chloride (60 mL) was addedboron tribromide (1.0 M in methylene chloride, 10 mL). The reactionmixture was stirred at room temperature overnight. The reaction wasquenched with methanol (3.0 mL), poured into water and extracted withethyl acetate. The organic layer was dried, concentrated and purified bysilica gel chromatography eluting with 25% ethyl acetate in hexane toprovide the compound (P-0067, 180 mg, 44%). MS (ESI) [M−H⁺]⁻=333.0,335.0.

2-Fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenolP-0778

was prepared using the protocol of Scheme 10, Step 2, replacing(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl)-methanoneP-0265 with3-(2-Fluoro-3-methoxy-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine(P-0269, prepared as described in Example 10, Scheme 24). MS (ESI)[M+H⁺]⁺=320.2.

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-5-hydroxy-phenyl)-methanoneP-0068

was prepared using the protocol of Scheme 10, replacing2-Fluoro-3-methoxy-benzoyl chloride 34 with 2-Fluoro-5-methoxy-benzoylchloride (prepared from the corresponding carboxylic acid using theprotocol of Example 1, Scheme 13, Step 4) in Step 1. MS (ESI)[M−H⁺]⁺=347, 349.

Example 54 Synthesis of(2-fluoro-3-hydroxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0036

Compound P-0036 was synthesized in three steps from(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-hydroxy-phenyl)-methanoneP-0067 as shown in Scheme 11.

Step 1—Preparation of 5-bromo-3(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-pyrrolo[2,3b]pyridine-1-carboxylicacid tert-butyl ester (32)

To(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-hydroxy-phenyl)-methanone(P-0067, 310.0 mg, 0.93 mmol, prepared as described in Example 53,Scheme 10) in tetrahydrofuran (40 mL) were added sodium hydride (60%dispersion, 81.4 mg, 2.04 mmol) and di-tert-butyldicarbonate (0.50 g,2.3 mmol). The reaction was stirred at room temperature for 1 hour. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,concentrated and purified by silica gel chromatography, eluting with 20%ethyl acetate in hexane to provide the compound (32, 0.45 g, 91%).

Step 2—Preparation of3-(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-5-phenyl-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (33)

To5-bromo-3-(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (32, 55.0 mg, 0.10 mmol) in tetrahydrofuran (10mL) were added 1.0 M potassium carbonate in water (3.5 mL),phenylboronic acid (18.8 mg, 0.15 mmol) andtetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) under anatmosphere of nitrogen. The reaction was stirred at 65° C. for 3 hours,and then poured into water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate, and concentratedto give crude compound 33 that was used in the next step.

Step 3—Preparation of(2-fluoro-3-hydroxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0036)

To3-(3-tert-butoxycarbonyloxy-2-fluoro-benzoyl)-5-phenyl-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (33, 30.0 mg, 0.056 mmol) in methylene chloride(6.0 mL) was added 4 N HCl in dioxane (2.0 mL). The reaction was stirredat room temperature for 36 hours. Solvents were removed by evaporation.The residue was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate,concentrated and purified by silica gel chromatography, eluting with 25%ethyl acetate in hexane to give a white solid (P-0036, 4.8 mg, 24%). MS(ESI) [M+H⁺]⁺=333.2.

Additional compounds were prepared following the protocol of Scheme 11,optionally replacing(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-hydroxy-phenyl)-methanoneP-0067 with(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-2-methyl-phenyl)-methanoneP-0055 (prepared as described in Example 56, Scheme 22) in Step 1 andoptionally replacing phenylboronic acid with an appropriate boronic acidin Step 2. The following compounds were made following this procedure:

-   N-{3-[3-(2-Fluoro-3-hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide    (P-0035),-   N-{3-[3-(2-Fluoro-3-hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide    (P-0038),-   3-[3-(2-Fluoro-3-hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzamide    (P-0034),-   (3-Hydroxy-2-methyl-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methanone    (P-0006),-   (3-Hydroxy-2-methyl-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3b]pyridin-3-yl)-methanone    (P-0114),-   (3-Hydroxy-2-methyl-phenyl)-(5-phenyl-1H-pyrrolo[2,3b]pyridin-3-yl)-methanone    (P-0016),-   (2-Fluoro-3-hydroxy-phenyl)-[5-(3-methanesulfonylphenyl)1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone    (P-0026),-   (2-fluoro-3-hydroxy-phenyl)-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0744), and-   [5-(3-amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-3-hydroxy-phenyl)methanone    (P-0004).    The following table indicates the boronic acid (column 2) and the    5-Br azaindole (column 3) used to afford the compound (column 4).    Column 1 provides the compound number and column 5 the observed    mass.

MS (ESI) [M + H⁺]⁺ Boronic acid 5-Br azaindole Compound observed P-0035

390.2 P-0038

426.1 P-0034

376.1 P-0006

330.2 P-0114

335.1 P-0016

329.2 P-0026

411.0 P-0744

335.1 P-0004

348.1

Example 55 Synthesis of(2,6-Difluoro-3-hydroxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0066

Compound P-0066 was synthesized in six steps from 2,4-difluoro-phenol 35as shown in Scheme 12.

Step 1—Preparation of tert-butyl-(2,4-difluoro-phenoxy)-dimethyl-silane(36)

To 2,4-difluoro-phenol (35, 5.00 g, 38.4 mmol) in N,N-dimethylformamide(100 mL) were added tert-butyldimethylsilyl chloride (7.00 g, 46.4 mmol)and imidazole (6.28 g, 92.2 mmol). The reaction was stirred at roomtemperature overnight. The reaction was poured into water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and filtrated. The filtrate was concentratedand purified by silica gel column chromatography eluting with 10% ethylacetate in hexane. The appropriate fractions were combined andconcentrated to provide the compound (36, 7.50 g, 80.0%). MS (ESI)[M+H⁺]⁺=245.1.

Step 2—Preparation of3-(tert-butyl-dimethyl-silanyloxy)-2,6-difluoro-benzaldehyde (37)

To tert-butyl-(2,4-difluoro-phenoxy)-dimethyl-silane (36, 5.90 g, 24.1mmol) in tetrahydrofuran (100 mL), under an atmosphere of nitrogen,cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50M in hexane, 10.6 mL, 26.5 mmol) slowly. The reaction was allowed tostir for 1 hour, then N,N-dimethylformamide (2.24 mL, 29.0 mmol) wasadded and the reaction was allowed to warm to room temperatureovernight. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated. The compound was isolated bysilica gel column chromatography eluting with 10% ethyl acetate inhexane to give a colorless oil (37, 5.0 g, 76.0%). MS (ESI)[M+H⁺]⁺=272.2.

Step 3—Preparation of 2,6-difluoro-3-hydroxy-benzaldehyde (38)

To 3-(tert-butyl-dimethyl-silanyloxy)-2,6-difluoro-benzaldehyde (37,3.50 g, 12.9 mmol) in N,N-dimethylformamide (50 mL) was addedtetrabutylammonium fluoride trihydrate (4.40 g, 14.0 mmol). The reactionwas stirred at room temperature for 1 hour. The reaction mixture waspoured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated to give crude compound 38 that was used in the next step.

Step 4—Preparation of carbonic acid tert-butyl ester 2,4-difluoro-3formyl-phenyl ester (39)

To 2,6-difluoro-3-hydroxy-benzaldehyde (38, 1.90 g, 12.0 mmol) intetrahydrofuran (60 mL) was added sodium hydride (60% in mineral oil,0.58 g, 14.5 mmol) and di-tert-butyldicarbonate (3.90 g, 17.9 mmol). Thereaction was stirred at room temperature overnight. The reaction mixturewas poured into water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated. The desired compound was isolated by silica gel columnchromatography eluting with 10% ethyl acetate in hexane to give acolorless oil (39, 2.50 g, 80.8%). MS (ESI) [M+H⁺]⁺=258.1.

Step 5—Preparation of2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol(P-0009)

To carbonic acid tert-butyl ester 2,4-difluoro-3-formyl-phenyl ester(39, 0.405 g, 15.7 mmol) in methanol (36 mL), under an atmosphere ofnitrogen, was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 288.0mg, 14.8 mmol, prepared as in Example 17, Scheme 32) and potassiumhydroxide (145.0 mg, 25.9 mol). The reaction was stirred at roomtemperature overnight. The reaction was poured into water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated. The desired compound wasisolated by silica gel column chromatography eluting with 4% methanol inmethylene chloride to give a colorless oil (P-0009, 0.23 g, 44.1%). MS(ESI) [M+H⁺]⁺=354.1.

Step 6—Preparation of(2,6-difluoro-3-hydroxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0066)

To2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol(P-0009, 45.0 mg, 1.27 mmol) in tetrahydrofuran (15 mL) andN,N-dimethylformamide (5 mL) was added dichlorodicyanoquinone (87 mg,3.8 mmol). The reaction was stirred at room temperature for 50 hours.The reaction was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated. The desired compound was isolated by silica gel columnchromatography eluting with 5% methanol in methylene chloride to give awhite solid (P-0066, 7 mg, 15.6%). MS (ESI) [M+H⁺]⁺=352.1.

(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-difluoro-3-hydroxy-phenyl)-methanoneP-1271

was prepared following the protocol of Scheme 12, substituting5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with5-bromo-1H-pyrrolo[2,3-b]pyridine 67 in Step 5. This was reacted further(70.0 mg, 0.20 mmol) in methylene chloride (15 mL) by adding pyridine(0.50 mL, 6.2 mmol), propane-1-sulfonyl chloride (0.50 g, 3.5 mmol) and4-dimethylaminopyridine (0.10 g, 0.82 mmol). The reaction was stirred atroom temperature overnight. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated. Thecompound, propane-1-sulfonic acid3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylester P-0919

was isolated by silica gel column chromatography eluting with 10% ethylacetate in hexane to give a white solid (15 mg, 16%). MS (ESI)[M−H⁺]⁻=456.9, 458.9.

Example 56 Synthesis of(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-2-methyl-phenyl)-methanoneP-0055

Compound P-0055 was synthesized in two steps from 5-Bromo-7-azaindole 67as shown in Scheme 22.

Step 1—Preparation of acetic acid3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl ester(84)

To aluminum trichloride (6.14 g, 0.046 mol) in methylene chloride (26mL) under an atmosphere of nitrogen was added 5-Bromo-7-azaindole (67,1.05 g, 5.31 mmol) dissolved in methylene dichloride (20.0 mL). Thereaction was stirred at room temperature for 65.0 minutes, then aceticacid 3-chlorocarbonyl-2-methyl-phenyl ester (1.25 g, 5.88 mmol) inmethylene dichloride (7.0 mL) was added. The reaction was stirred for 2hours at room temperature, poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated to give crude compound 84 that was useddirectly in the next step.

Step 2—Preparation of(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-2-methyl-phenyl)-methanone(P-0055)

A solution of acetic acid3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl ester(84, 25.0 mg, 0.067 mmol) in 6 N HCl (4.0 mL) was heated with a CEMDiscover microwave instrument at 110° C. for 10 min. The reactionmixture was poured into water, neutralized with 1 M aqueous potassiumcarbonate, and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate and concentrated.The desired compound was isolated by silica gel column chromatographyeluting with 10% ethyl acetate in hexane to give a colorless oil(P-0055, 4.7 mg, 21%). MS (ESI) [M−H⁺]⁻=329.0, 331.0.

Example 57 Synthesis of2-Fluoro-3-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenolP-0052

Compound P-0052 was synthesized in five steps from(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl)-methanoneP-0265 as shown in Scheme 23.

Step 1—Preparation of5-bromo-3-(2-fluoro-3-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (86)

To(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl)-methanone(P-0265, 600.0 mg, 1.72 mmol, prepared as described in Example 1 or 53)in tetrahydrofuran (20 mL) was added sodium hydride (60% dispersion, 103mg, 2.58 mmol) under an atmosphere of nitrogen. After 15 minutes,di-tert-butyldicarbonate (648 mg, 2.97 mmol) was added. The reactionmixture was stirred at room temperature for 1 hour, poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated. The desiredcompound was isolated by silica gel column chromatography eluting with10% ethyl acetate in hexane to give a colorless oil (86, 0.64 g, 82.3%).

Step 2—Preparation of3-(2-fluoro-3-methoxy-benzoyl)-5-thiophen-2-yl-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (87)

To5-bromo-3-(2-fluoro-3-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (86, 350.0 mg, 0.78 mmol) in tetrahydrofuran (30mL) and water (10 mL) were added 2-thiophene boronic acid (190 mg, 1.49mmol), tetrakis(triphenyl-phosphine)palladium(0) (40.0 mg, 0.0346 mmol)and potassium carbonate (780 mg, 5.64 mmol) under an atmosphere ofnitrogen. The reaction mixture was refluxed for 2 hours. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated to give crude compound (87, 0.30 g, 85%).

Step 3—Preparation of(2-fluoro-3-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0521)

To3-(2-fluoro-3-methoxy-benzoyl)-5-thiophen-2-yl-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (87, 200 mg, 0.44 mmol) in methylene chloride (10mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone dryice bath, was added boron tribromide (1.0 M in hexane, 2.0 mL). Thereaction mixture was allowed to warm to room temperature and stirredovernight. The reaction was quenched with methanol (3.0 mL), poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and concentrated. Thedesired compound was isolated by silica gel column chromatographyeluting with 5% methanol in methylene chloride to give a white solid(P-0521, 119 mg, 82.6%). MS (ESI) [M−H⁺]⁺=337.

Step 4—Preparation of2-Fluoro-3-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl-phenol(P-0052)

To(2-fluoro-3-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0521, 50.0 mg, 0.15 mmol) in diethylene glycol (5.0 mL) were addedhydrazine hydrate (1.0 mL, 0.020 mol) and potassium hydroxide (200.0 mg,3.56 mmol). The reaction mixture was heated in a CEM Discovery microwaveinstrument at 180° C. for 20 minutes, poured into water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated. The desired compound wasisolated by silica gel column chromatography eluting with 5% methanol inmethylene chloride to give a white solid (P-0052, 10 mg, 20%). MS (ESI)[M+H⁺]⁻=325.2.

Example 58 Synthesis of (2,4-Difluoro-3-formyl-phenyl)-carbamic acidtert-butyl ester 124

(2,4-Difluoro-3-formyl-phenyl)-carbamic acid tert-butyl ester 124 wassynthesized in two steps from 2,4-Difluoro-phenylamine 42 as shown inScheme 25.

Step 1—Preparation of (2,4-Difluoro-phenyl)-carbamic acid tert-butylester (123)

To 2,4-difluoro-phenylamine (42, 5.0 g, 0.039 mol) in methylene chloride(100 mL) were added di-tert-butyldicarbonate (21.1 g, 0.0968 mol),triethylamine (16 mL, 0.12 mol) and 4-dimethylaminopyridine (0.2 g,0.002 mol). The reaction was stirred at room temperature overnight,poured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, concentrated andpurified by silica gel chromatography, eluting with 20% ethyl acetate inhexane to provide compound 123.

Step 2—Preparation of (2,4-Difluoro-3-formyl-phenyl)-carbamic acidtert-butyl ester (124)

To 2,4-difluoro-phenyl)-carbamic acid tert-butyl ester (123, 1.41 g,6.17 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogenat 78° C. were added n-butyllithium (2.50 M in hexane, 2.59 mL) for 30min. Lithium diisopropylamide (2.0 M in hexane, 3.4 mL) was added to thereaction. After 35 min, N,N-dimethylformamide (1.05 mL, 0.0136 mol) wasadded to the reaction mixture. The reaction was allowed to cool to roomtemperature overnight. The organic layer was washed with brine, driedover sodium sulfate, concentrated and purified by silica gelchromatography, eluting with 20% ethyl acetate in hexane to providecompound 124.

Example 59 Synthesis of1-[4-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-ureaP-0262

Compound P-0262 was synthesized in seven steps from1H-Pyrrolo[2,3-b]pyridine 94 as shown in Scheme 34.

Step 1—Preparation ofDimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine (109)

1H-Pyrrolo[2,3-b]pyridine (94, 5.0 g, 42 mmol), dimethylaminehydrochloride (3.8 g, 46 mmol), formaldehyde (1.4 g, 46 mmol) andisopropyl alcohol (220.0 mL) were combined in a pressure tube. Thereaction mixture was stirred at 20° C. for 12 hours and then refluxedfor 2 hours. The clear solution was evaporated to dryness in vacuo.Water (40 mL) and concentrated hydrochloric acid (4 mL) were added tothe residue. The mixture was extracted with ether and then made stronglybasic with potassium carbonate. The basified aqueous layer was extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, concentrated and purified by silica gel chromatographyto give the compound (109, 5.0 g, 68%).

Step 2—Preparation ofDimethyl-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine(110)

Dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 109 (5.0 g, 28mmol), was dissolved in N,N-dimethylformamide (80.0 mL) and sodiumhydride (60% dispersion in mineral oil, 1.25 g, 31.4 mmol) was added,followed by triisopropylsilyl chloride (6.3 mL, 30.0 mmol). The reactionwas stirred at room temperature for 12 hours, then poured into water andextracted with ethyl acetate. The organic portion was washed with brine,dried over sodium sulfate, concentrated and purified with silica gelchromatography to give the compound (110, 6.5 g, 70%).

Step 3—Preparation of3-(4-Bromo-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (111)

1-bromo-4-iodobenzene (2.1 g, 7.4 mmol) was dissolved in tetrahydrofuran(15.0 mL) under an atmosphere of nitrogen at −30° C. Isopropylmagnesiumchloride in tetrahydrofuran (2.0 M, 4.0 mL) was added. The reactionmixture was stirred below −20° C. for 1 hour to provide a solution of1-bromo-4-benzene magnesium chloride.

Dimethyl-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine110 (1.25 g, 3.77 mmol) was added to toluene (20.0 mL) under anatmosphere of nitrogen at room temperature. Isopropyl chloroformate intoluene (1.0 M, 4.0 mL) was added, The reaction mixture was stirred atroom temperature for 3 hours to provide a solution of3-chloromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine.

CuCN.2LiCl in tetrahydrofuran (0.7 M, 10 mL) was added to the solutionof 1-bromo-4-benzene magnesium chloride at −20° C. The reaction mixturewas allowed to warm to room temperature for 10 minutes. Trimethylphosphite (1.8 mL, 0.015 mol) was added to the reaction. After 5minutes, the solution of3-chloromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine was addedto the reaction at room temperature. The reaction was stirred for 12hours at room temperature. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, concentrated and purified with silicagel chromatography to give the compound (111, 850 mg, 51%).

Step 4—Preparation ofBenzyl-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amine(112)

3-(4-Bromo-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (111,330.0 mg, 0.74 mmol), benzylamine (160 mg, 1.5 mmol),2-[di(tert-butyl)phosphino]-1,1′-biphenyl (15.0 mg, 0.05 mmol),tris(dibenzylideneacetone)dipalladium(0) (15.0 mg, 0.016 mmol),potassium tert-butoxide (100 mg, 0.89 mmol) and toluene (10.0 mL) werecombined under an atmosphere of nitrogen. The reaction mixture wasrefluxed overnight, then poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, concentrated and purified with silica gel chromatography togive the compound (112, 260 mg, 75%).

Step 5—Preparation of4-(1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenylamine(113)

Benzyl-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amine(112, 210.0 mg, 0.447 mmol), methanol (15.0 mL) and palladium hydroxide(30.0 mg, 0.214 mmol) were combined. The reaction mixture washydrogenated under an atmosphere of hydrogen (1 atm) at room temperaturefor 2 hours. Filtration and concentration gave the compound (113, 154mg, 91%).

Step 6—Preparation of1-3-Trifluoromethyl-phenyl)-3-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-urea(114)

4-(1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenylamine(113, 70.0 mg, 0.184 mmol) was dissolved in tetrahydrofuran (12 mL) and3-trifluoromethyl-phenyl isocyanate (41 mg, 0.22 mmol) and triethylamine(28 mg, 0.28 mmol) were added under an atmosphere of nitrogen. Thereaction mixture was stirred at room temperature overnight, then pouredinto water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, concentrated to give crudecompound 114 used in the next step.

Step 7—Preparation of1-[4-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea(P-0262)

1-(3-Trifluoromethyl-phenyl)-3-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-urea(114, 85.0 mg, 0.150 mmol) was dissolved in tetrahydrofuran (10.0 mL)and tetra-n-butylammonium fluoride (52.2 mg, 0.200 mmol) was added.After 10 minutes, the reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, concentrated and purified with by silica gelchromatography to give the compound (P-0262, 23 mg, 38% over steps 6 &7). MS (ESI) [M+H⁺]⁺=411.2

Example 60 Synthesis of(4-Hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0024

Compound P-0024 was synthesized in four steps from 5-bromo-7-azaindole67 as shown in Scheme 35.

Step 1—Preparation of(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(4-methoxy-phenyl)-methanone(116)

Aluminum trichloride (2.7 g, 20.0 mmol) and methylene chloride (30 mL)were combined under an atmosphere of nitrogen and 5-bromo-7-azaindole(67, 400.0 mg, 2.30 mmol) in methylene dichloride (20 mL) was added. Thereaction was stirred at room temperature for 70 minutes.4-Methoxybenzoic acid chloride (0.38 g, 2.2 mmol) (prepared from thecorresponding carboxylic acid using the protocol described in Example 1,Scheme 13, Step 4) in methylene dichloride (7.0 mL) was added. Thereaction was stirred at room temperature for 2 hours, then poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, and concentrated to give thecompound (116, 250 mg, 34%).

Step 2—Preparation of5-Bromo-3-(4-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (117)

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(4-methoxy-phenyl)-methanone(116, 220.0 mg, 0.66 mmol) was dissolved in tetrahydrofuran (15.0 mL)and sodium hydride (60% dispersion, 29 mg, 0.73 mmol) was added under anatmosphere of nitrogen. The reaction was stirred for 15 minutes.Di-tert-butyldicarbonate (220 mg, 1.0 mmol) was added. The reaction wasstirred for one hour, then poured into water and extracted with ethylacetate. The organic portion was washed with brine, dried over sodiumsulfate and concentrated to give compound 117.

Step 3—Preparation of3-(4-Methoxy-benzoyl)-5-thiophen-2-yl-pyrrolo[2,3-j]pyridine-1-carboxylicacid tert-butyl ester (118)

5-Bromo-3-(4-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (117, 100.0 mg, 0.23 mmol), thiophene-2-boronic acid(59 mg, 0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (20.0 mg,0.017 mmol), potassium carbonate (80 mg, 0.58 mmol), tetrahydrofuran(15.0 mL) and water (5.0 mL) were combined under an atmosphere ofnitrogen. The reaction mixture was refluxed overnight, then poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, concentrated and purified withsilica gel chromatography to give compound 118 (100 mg).

Step 4—Preparation of(4-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0024)

3-(4-Methoxy-benzoyl)-5-thiophen-2-yl-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (118, 100.0 mg, 0.23 mmol) and methylene chloride(15.0 mL) were combined under an atmosphere of nitrogen. Borontribromide (1.0 M in methylene chloride, 3.0 mL) was added. The reactionwas stirred at room temperature overnight. Methanol (2.0 mL) was addedinto the reaction mixture. The reaction was concentrated to removesolvents. The residue was extracted with water and ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate,concentrated and purified with silica gel chromatography. The productwas washed with methanol to provide compound (P-0024, 25.0 mg, 34%). MS(ESI) [M+H⁺]⁺=321.

Example 61 Synthesis of4-Benzofuran-2-yl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethylester P-1248

Compound P-1248 was synthesized in four steps from 4-chloro-7-azaindole119 as shown in Scheme 36,

Step 1—Preparation of 4-Benzofuran-2-yl-1H-pyrrolo[2,3-b]pyridine (120)

4-Chloro-7-azaindole (119, 100 mg, 0.66 mmol, prepared as described inExample 70, Scheme 81), 2-Benzofuranboronic acid (212 mg, 1.31 mmol) andPotassium fluoride (127 mg, 2.18 mmol) were stirred in 3 mL of anhydrousdioxane. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct(10.2 mg, 9.83E-3 mmol) and tri t-butylphosphine (6.6 mg, 0.033 mol)were added and the suspension was stirred at 100° C. for 4 hours in apressure tube under inert atmosphere. The reaction mixture was cooled toroom temperature and was adsorbed onto silica gel and purified bychromatography to provide the compound (120, 56 mg, 36%). MS (ESI)[M+H⁺]⁺=235.20.

Step 2—Preparation of1-Benzenesulfonyl-4-benzofuan-2-yl-1H-pyrrolo[2,3-b]pyridine (121)

Into a Round bottom flask 4-benzofuran-2-yl-1H-pyrrolo[2,3-b]pyridine(120, 100 mg, 0.43 mmol) was suspended in methylene chloride (10 mL) and50% KOH solution (5 mL) was added. Tetrabutylammonium hydrogen sulfate(10 mg, 0.03 mmol) and benzenesulfonyl chloride (81.4 mg, 0.46 mmol)were added. The resulting yellow solution was stirred at ambienttemperature for 2 hours. The reaction mixture was partitioned betweenethyl acetate and water and the organic layer was separated and washedwith water and brine then dried over MgSO₄, filtered and concentratedunder reduced pressure to provide compound 121. MS (ESI) [M+H⁺]⁺=375.29.

Step3—1-Benzenesulfonyl-4-benzofuran-2-yl-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid ethyl ester (122)

To a chilled (−78° C. acetone/dry ice bath) solution of1-benzenesulfonyl-4-benzofuran-2-yl-1H-pyrrolo[2,3-b]pyridine (121, 66.0mg, 0.18 mmol) in tetrahydrofuran (5.0 mL) under an atmosphere ofnitrogen, n-butyllithium (1.6 M in tetrahydrofuran, 0.14 mL, 0.23 mmol)was added dropwise. The reaction mixture was stirred for 30 minutes andethyl chloroformate (0.02 mL, 0.19 mmol) was added. The reaction mixturewas stirred for 1 hour while allowing it to reach room temperature,poured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure and purified bysilica gel column chromatography, eluting with 20% ethyl acetate inhexane, to give light yellow solid (122, 0.015 g, 19%). MS (ESI)[M+H⁺]⁺=447.3.

Step 4-4-Benzofuran-2-yl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acidethyl ester (P-1248)

To a solution of1-benzenesulfonyl-4-benzofuran-2-yl-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid ethyl ester (122, 14.0 mg, 0.03 mmol) in tetrahydrofuran (3.0 mL),was added tetra N-butylammonium fluoride (26.0 mg, 0.10 mmol). Thereaction was stirred for 48 hours at room temperature, then poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure and purified by silicagel column chromatography, eluting with 50% Ethyl acetate in hexane, togive light yellow solid (P-1248, 3.0 mg, 36%). MS (ESI) [M+H⁺]⁻=307.2.

Example 62 Synthesis of N-phenyl-1H-pyrrolo[2,3-b]pyridin-6-amine P-1350and related compounds

Compound P-1350 was synthesized in five steps from1H-pyrrolo[2,3-b]pyridine 94 as shown in Scheme 40.

Step 1—Preparation of 1H-pyrrolo[2,3-b]pyridine-N-oxide (585)

To 1H-pyrrolo[2,3-b]pyridine (94, 3.0 g, 25.3 mmol) dissolved in 175 mLof diethyl ether was added m-CPBA (1.5 equiv) in portions over 30minutes with vigorous stirring. The solution turned yellow, andprecipitates formed. After two hours the solid was collected, washedwith 2×50 mL of ether, and recrystallized from acetone:ether. Yield wasapproximately 125% due to contaminating acid. This crude material wascarried through to the next step.

Step 2-(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone (586)

1H-pyrrolo[2,3-b]pyridine-N-oxide (585, 500 mg, 3.72 mmol) was dissolvedin 40 mL of dry benzene. In a separate dry flask, benzoyl bromide (2.5equiv) and 1,1,1,3,3,3-hexamethyldisilazane (1.0 equiv) were combined in20 mL of dry benzene. The bromide solution was added in 5 mL aliquotsover 30 minutes to the reaction flask. The reaction was stirred atambient temperature for two hours. It was then washed with 3×30 mLNaHCO₃ (aq., satd.) and 1×30 mL brine. The organic layer was dried oversodium sulfate and evaporated. The crude material was taken directly tothe next step without further purification.

Step 3—Preparation of 6-bromo-1H-pyrrolo[2,3-b]pyridine (587)

(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone, 586 wasdissolved in 20 mL of dioxane and 20 mL of 2M KOH (aq). This was stirredat ambient temperature until analysis indicated all of the startingmaterial had been consumed (2 to 4 hours). The reaction was diluted with50 mL of ethyl acetate and washed with 2×25 mL of NaHCO₁ (aq. satd.) and25 mL of brine. The organic layer was dried with sodium sulfate,evaporated and purified by column chromatography. Combined steps 2 and 3gave approximately 65% overall yield.

Step 4—Preparation of6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (588)

6-bromo-1H-pyrrolo[2,3-b]pyridine (587, 275 mg, 1.39 mmol) was dissolvedin 4 mL of dry dioxane. DIEA (3 equiv) and TIPS-OTf (2.5 equiv) wereadded and the reaction was stirred at 50° C. overnight. The reaction wasthen diluted with 20 mL of ethyl acetate and washed 2 times with 10 mLNaHCO₃ (aq., 5%) and once with 10 mL brine. The organic fraction wasdried over MgSO₄, evaporated and diluted with 5.5 mL of dry toluene (˜10mg bromide per 0.2 mL of solution) to use directly in the next reactionstep.

Step 5—Preparation of N-phenyl-1H-pyrrolo[2,3-b]pyridin-6-amine (P-1350)

A 1 dram vial was charged with aniline (2-3 equiv), and 0.200 mL of the588 stock solution of bromide in toluene was added. A catalyst stocksolution containing 3 mmol Pd(OAc)₂, 3 mmolbiphenyl-2-yl-di-tert-butyl-phosphane and 15 mL of toluene was preparedand 0.050 mL of the catalyst solution was added to the reaction. Anexcess of NaOtBu was added as a solid to the reaction. The vial wasplaced in an 80° C. oven for 60 minutes (shaken several times over thehour). After cooling, the reaction was neutralized with 0.100 mL of TFA.After 30 minutes the sample was evaporated and resolvated in 0.300 mL ofDMSO. The desired compound was isolated by preparative HPLC/MS. MS (ESI)[M+H⁺]⁺=210.4.

The following compounds were prepared following the protocol of scheme40, substituting aniline with a suitable amine is Step 5:

-   Cyclohexyl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1290),-   Benzyl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1291),-   Cyclopropylmethyl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1292),-   (3-Methoxy-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1293),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(3-trifluoromethyl-benzyl)-amine    (P-1294),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(2-trifluoromethyl-benzyl)-amine    (P-1295),-   Cyclohexylmethyl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1296),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(4-trifluoromethoxy-benzyl)-amine    (P-1297),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(3-trifluoromethoxy-benzyl)-amine    (P-1298),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(2-trifluoromethoxy-benzyl)-amine    (P-1299),-   Pyridin-2-ylmethyl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1300),-   (4-Methanesulfonyl-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1301),-   (4-Methoxy-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1302),-   Ethyl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1303),-   (3-Chloro-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1304),-   (4-Methyl-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1305),-   (1-Methyl-piperidin-4-yl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1306),-   Pyridin-3-ylmethyl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1307),-   [4-(Morpholine-4-sulfonyl)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1308),-   (4-Methanesulfonyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1309),-   (2-Chloro-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1310),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(tetrahydro-pyran-4-yl)-amine    (P-1311),-   (4-Chloro-benzyl)-(H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1312),-   (3-Methyl-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1313),-   [3-(Morpholine-4-sulfonyl)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1314),-   (3-Methanesulfonyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1315),-   Pyridin-3-yl-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1351),-   (2-Methoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1352),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(3-trifluoromethyl-phenyl)-amine    (P-1353),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(4-trifluoromethoxy-phenyl)-amine    (P-1354),-   (4-Methoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1355),-   N,N-Dimethyl-N′-(1H-pyrrolo[2,3-b]pyridin-6-yl)-benzene-1,4-diamine    (P-1356),-   (3-Methoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1357),-   (4-Morpholin-4-yl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1358),-   (4-Piperidin-1-yl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1359),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(3-trifluoromethoxy-phenyl)-amine    (P-1360),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-p-tolyl-amine (P-1361),-   (3-tert-Butyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1362),-   (3-Dimethylamino-benzyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1363),-   (3,5-Dichloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1364),-   (1H-Pyrrolo[2,3-b]pyridin-6-yl)-(4-trifluoromethyl-benzyl)-amine    (P-1371),-   N,N-Dimethyl-N′-(1H-pyrrolo[2,3-b]pyridin-6-yl)-benzene-1,3-diamine    (P-1372),-   (3-Chloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1373),-   (4-Chloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1374),-   (2-Chloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine (P-1375),-   (5-Methyl-isoxazol-3-yl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1376),-   (2-Morpholin-4-yl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1377), and-   (2-Methanesulfonyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-6-yl)-amine    (P-1378).    The following table indicates the amine (Column 2) that is    substituted in place of the aniline in Step 5 to afford the compound    (Column 3). Column 1 provides the compound number and Column 4 the    observed mass.

Com- MS (ESI) pound [M + H⁺]⁺ number Amine Compound structure observedP-1290

216.3 P-1291

224.3 P-1292

188.2 P-1293

254.3 P-1294

291.9 P-1295

291.9 P-1296

230.3 P-1297

308.3 P-1298

308.3 P-1299

308.3 P-1300

225.1 P-1301

302.3 P-1302

254.3 P-1303

162.2 P-1304

258.3 P-1305

238.3 P-1306

231.1 P-1307

225.1 P-1308

359.1 P-1309

287.9 P-1310

258.3 P-1311

218.3 P-1312

258.3 P-1313

238.3 P-1314

359.1 P-1315

287.9 P-1351

211.0 P-1352

240.3 P-1353

278.3 P-1354

293.9 P-1355

240.3 P-1356

253.1 P-1357

240.3 P-1358

295.1 P-1359

293.1 P-1360

293.9 P-1361

224.3 P-1362

266.3 P-1363

267.1 P-1364

278.3 P-1371

291.9 P-1372

253.1 P-1373

244.3 P-1374

244.3 P-1375

244.3 P-1376

215.0 P-1377

295.1 P-1378

287.9

Example 63 Synthesis of2-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-ethanolP-1395 and related compounds

Compound P-1395 was synthesized in four steps from4-Chloro-2-fluoro-phenol 521 as shown in Scheme 42.

Step 1—Preparation of4-Chloro-2-fluoro-1-(2,2,2-trifluoro-ethoxy)-benzene (522)

To 4-Chloro-2-fluoro-phenol (521, 5.0 g, 0.034 mol) in methanol (50.0mL) was added potassium fluoride (2.2 g, 0.038 mol). The solvent wasremoved. The resulting salt was added to N,N-dimethylformaldehyde (25mL), followed by adding 1,1,1-trifluoro-2-iodo-ethane (8.60 g, 40.9mmol). The reaction was stirred at 50° C. overnight. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% ethyl acetate in hexane to give colorless oil (522, 2.0 g,26%).

Step 2—Preparation of6-Chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (523)

To 4-Chloro-2-fluoro-1-(2,2,2-trifluoro-ethoxy)-benzene (522, 0.80 g,3.5 mmol) in THF (20 mL), cooled in dry ice/acetone bath and under anatmosphere of nitrogen, was slowly added n-butyllithium (1.60 M inHexane, 2.30 mL). After an hour, N,N-dimethylformamide (0.298 mL, 3.85mmol) was added to the reaction. After 30 minutes, the reaction wasallowed to reach room temperature and was stirred for 10 minutes. Thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% ethyl acetate in hexane to give thecompound (523, 450 mg, 50%).

Step 3—Preparation of(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-methanol(524)

To 5-bromo-7-azaindole (67, 291 mg, 1.48 mmol) in methanol (22 mL) wereadded 6-Chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (523,400.0 mg, 1.6 mmol) and potassium hydroxide (1.49 g, 26.6 mmol) under anatmosphere of nitrogen. The reaction was stirred at room temperature for48 hours. The reaction was poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 25% ethyl acetate in hexane to givethe compound (524, 300 mg, 42%). MS (ESI) [M+H⁺]⁺=453.1, 455.1.

Step 4—Preparation of(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-methanol(P-1393)

To(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-methanol(524, 140.0 mg, 0.31 mmol) in tetrahydrofuran (6.0 mL) was addedDess-Martin periodinane (157 mg, 0.37 mmol). The reaction was stirred atroom temperature for 10 minutes. The reaction was poured into water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 20% ethyl acetate inhexane to give the compound (P-1393, 100 mg, 72%). MS (ESI)[M−H+]−=448.9, 450.9.

Step 5—Preparation of[6-Chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1395)

To(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-methanol(P-1393, 53.0 mg, 0.12 mmol) in acetonitrile (4.0 mL) was addedTetrakis(triphenylphosphine)palladium(0) (5.0 mg, 0.0043 mmol),3-pyridylboronic acid (15.1 mg, 0.12 mmol) and 1 M potassium carbonatesolution (1.5 mL). The reaction was microwaved (300 watts) at 160° C.for 7 minutes. The reaction was poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 60% ethyl acetate in hexane to givethe compound (P-1395, 3.8 mg, 53%) as light yellow solid. MS (ESI)[M+H⁺]⁺=450.2.

[2,6-Difluoro-3-(2-methoxy-ethoxy)-phenyl]-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1456

was prepared following the protocol of Scheme 42, substituting4-Chloro-2-fluoro-phenol 521 with 2,4-difluoro-phenol and1,1,1-Trifluoro-2-iodo-ethane with 1-Bromo-2-methoxy-ethane in Step 1.MS (ESI) [M+H⁺]⁺=410.2.

N-(3-{3-[2,6-Difluoro-3-(2-methoxy-ethoxy)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenyl)-methanesulfonamideP-1472

was prepared following the protocol of Scheme 42, substituting4-Chloro-2-fluoro-phenol 521 with 2,4-difluoro-phenol and1.1.1-Trifluoro-2-iodo-ethane with 1-Bromo-2-methoxy-ethane in Step 1,and substituting pyridine-3-boronic acid with[(3-methylsulfonyl)aminophenyl]-boronic acid in step 4. MS (ESI)[M+H⁺]⁺=502.2.

Example 64 Synthesis of(3,5-Bis-difluoromethoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-1521

Compound P-1521 was synthesized in four steps from3,5-Dihydroxy-benzaldehyde 528 as shown in Scheme 44.

Step 1—Preparation of 3,5-Bis-difluoromethoxy-benzaldehyde (529)

To 3,5-Dihydroxy-benzaldehyde (528, 1.50 g, 10.9 mmol) inN,N-Dimethylformamide (100 mL) were added sodium chlorodifluoroacetate(5.90 g, 0.0387 mol), potassium carbonate (6.20 g, 0.0448 mol) and water(10 mL) under an atmosphere of nitrogen. The reaction was stirred at100° C. overnight. The reaction was poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% ethyl acetate in hexane to givethe compound as colorless oil (529, 50 mg, 2%).

Step 2—Preparation of(3,5-Bis-difluoromethoxy-phenyl)-(5-bromo-1-f-pyrrolo[2,3-b]pyridin-3-yl)-methanol(530)

To 5-bromo-7-azaindole (67, 86.4 mg, 0.000438 mol) in methanol (10.0 mL)were added 3,5-bis-difluoromethoxy-benzaldehyde (529, 110.0 mg, 0.46mmol) and potassium hydroxide (200.0 mg, 3.6 mmol) under an atmosphereof nitrogen. The reaction was stirred at room temperature overnight. Thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% ethyl acetate in hexane to give thecompound as a white solid (530, 70 mg, 35%). MS (ESI) [M+H⁺]⁺=435.1,437.1.

Step 3—Preparation of(3,5-Bis-difluoromethoxy-phenyl-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1519)

To (35-Bis-difluoromethoxy-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(530, 70.0 mg, 0.16 mmol) in tetrahydrofuran (6.0 mL) was addedDess-Martin periodinane (75.0 mg, 0.18 mmol). The reaction was stirredat room temperature for 10 minutes. The reaction mixture wasconcentrated with silica gel and purified with silica gel columnchromatography eluting with 30% ethyl acetate in hexane to give thecompound as a white solid (P-1519, 65.0 mg, 93%.). MS (ESI)[M−H⁺]⁻=431.0, 433.0.

Step 4—Preparation of(3,5-Bis-difluoromethoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1521)

To(3,5-Bis-difluoromethoxy-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-1519, 29.0 mg, 0.067 mmol) in acetonitrile (4.0 mL) were addedphenylboronic acid (12.2 mg, 0.10 mmol),Tetrakis(triphenylphosphine)palladium(0) (10.0 mg, 8.65E-6 mol) and 1.0M potassium carbonate in water (1.5 mL). The reaction was microwaved(300 watts) at 160° C. for 7 minutes. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, concentrated, and purifiedwith silica gel column chromatography to give the compound as a whitesolid (P-1521, 9.4 mg, 33%). MS (ESI) [M+H⁺]⁺=431.2.

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-difluoromethoxy-2,6-difluoro-phenyl)-methanoneP-1526

was prepared using Steps 1-3 of Scheme 44 by substituting3,5-Dihydroxy-benzaldehyde 528 with N-2,4-Difluoro-phenol in Step 1. MS(ESI) [M+H⁺]⁺=401.0, 403.0.

Example 65 Synthesis ofN-Benzyl-2-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-acetamideP-1469

Compound P-1469 was synthesized in four steps from3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridineP-1455 as shown in Scheme 46.

Step 1—Preparation of3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1-triisopropylsilanyl-H-pyrrolo[2,3-b]pyridine(548)

To3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine(P-1455, 700.0 mg, 1.64 mmol, prepared as described in Example 24,Scheme 43a) in tetrahydrofuran (40.0 mL) was added sodium hydride (60%in mineral oil, 100.0 mg, 2.5 mmol). After 10 minutes, triisopropylsilylchloride (0.60 mL, 0.0028 mol) was added to the reaction. The reactionwas stirred at room temperature for 2 hours. The reaction was pouredinto water and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% ethyl acetate in hexane to give the compound as colorless oil(548, 0.85 g, 89%).

Step 2—Preparation of2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol(549)

To3-(3-Benzyloxy-2,6-difluoro-benzyl)-5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(548, 510.0 mg, 0.87 mmol) in methanol (20.0 mL) was added 20% Pd(OH)₂/C(50 mg). The reaction was stirred under an atmosphere of hydrogen for 2hours. Filtration and concentration gave the compound as white solid(549, 427 mg, 99%).

Step 3—Preparation of[2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-acetic acid methyl ester (550)

To2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol(549, 427.0 mg, 0.87 mmol) in tetrahydrofuran (20.0 mL) was added sodiumhydride (60% in mineral oil, 42.0 mg, 1.1 mmol). 30 minutes later,methyl bromoacetate (146 mg, 0.95 mmol) was added to the reaction. Thereaction was stirred at room temperature for 4 hours. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated to give the crude compound that was used directly in thenext step.

Step 4—Preparation ofN-Benzyl-2-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-acetamide(P-1469)

To[2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-aceticacid methyl ester (550, 210.0 mg, 0.37 mmol) in methanol (6.0 mL) wasadded benzylamine (0.45 mL, 4.1 mmol). The reaction was stirred at roomtemperature for 80 hours. To the reaction was added TBAF (0.31 g, 1.0mmol). The reaction was concentrated and purified with silical gelcolumn chromatography eluting with 10% methanol in methylene chloride togive the compound as a white solid (P-1469, 60 mg, 33%). MS (ESI)[M+H⁺]⁺=423.3.

2-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-N-ethyl-acetamideP-1475

was prepared using the same protocol as Scheme 46 by substitutingbenzylamine with ethylamine in Step 4. MS (ESI) [M+H⁺]⁺=423.3.

Example 66 Synthesis of[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-aceticacid P-1468

Compound P-1468 was synthesized in two steps from[2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-aceticacid methyl ester 550 as shown in Scheme 47.

Step 1—Preparation of[4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-aceticacid methyl ester (P-1465)

To[2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-aceticacid methyl ester (550, 40.0 mg, 0.071 mmol, prepared as described inExample 65, Scheme 46) in tetrahydrofuran (5.0 mL) was addedtetra-n-butylammonium fluoride (22.2 mg, 0.085 mmol). The reaction wasstirred at room temperature for 10 minutes. The crude compound wasconcentrated with silica gel and purified by silica gel columnchromatography eluting with 3% methanol in methylene chloride to givethe compound as white solid (P-1465, 20 mg, 69%). MS (ESI)[M+H⁺]⁺=410.2.

Step 2—Preparation of[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-aceticacid (P-1468)

To[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-aceticacid methyl ester (P-1465, 20.0 mg, 0.049 mmol) in tetrahydrofuran (8.0mL) were added potassium hydroxide (100.0 mg, 1.8 mmol) and water (3.0mL). The reaction was stirred at room temperature overnight and thenpoured into water, acidified to pH=5 with 1 N HCl, and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 10% methanol in methylene chloride togive the compound as light yellow solid (P-1468, 9.1 mg, 47%). MS (ESI)[M+H⁺]⁺=396.2.

Example 67 Synthesis of2-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-ethanolP-1394

Compound P-1394 was synthesized in four steps from2,6-Difluoro-3-hydroxy-benzaldehyde 540 as shown in Scheme 48.

Step 1—Preparation of2,6-Difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzaldehyde (541)

To 2,6-difluoro-3-hydroxy-benzaldehyde (540, 0.150 g, 0.95 mmol) inN,N-dimethylformamide (8.0 mL) were added2-(2-bromo-ethoxy)-tetrahydro-pyran (0.218 g, 1.04 mmol) and potassiumcarbonate (0.52 g, 3.8 mmol) under an atmosphere of nitrogen. Thereaction was stirred at room temperature for 72 hours. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% ethyl acetate in hexane to give the compound as colorless oil(541, 180 mg, 66%).

Step 2—Preparation of(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-methanol(542)

To 5-bromo-7-azaindole (67, 118 mg, 0.000597 mol) in methanol (9.0 mL)were added2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzaldehyde (541,180.0 mg, 0.63 mmol) and potassium hydroxide (601.9 mg, 10.7 mmol) underan atmosphere of nitrogen. The reaction was stirred at room temperatureovernight. The reaction was poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated to give crude compound that wasused directly in the next step.

Step 3—Preparation of2-[3-(5-Bromo-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenoxy]-ethanol(P-1392)

To(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-methanol(542, 0.22 g, 0.46 mmol) in acetonitrile (6.0 mL) were addedtrifluoroacetic acid (0.14 mL, 1.8 mmol) and triethylsilane (0.29 mL,1.8 mmol). The reaction was stirred at room temperature overnight. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 35% ethyl acetate in hexane to give thecompound as a white solid (P-1392, 62 mg, 35%). MS (M+H⁺)⁺=383.1, 385.1.

Step 4—Preparation of2-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-ethanol(P-1394)

To2-[3-(5-Bromo-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenoxy]-ethanol(P-1392, 35.0 mg, 0.091 mmol) in acetonitrile (4.0 mL) were added3-pyridylboronic acid (14.6 mg, 0.12 mmol),tetrakis(triphenylphosphine)palladium(0) (3.0 mg, 0.0026 mmol) and 1 Mpotassium carbonate solution (1.5 mL). The reaction was microwaved (300watts) at 160° C. for 7 minutes. The reaction was poured into water andextracted with ethyl acetate. The organic layer was collected and driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography eluting 4%methanol in methylene chloride to give the compound as white solid(P-1394, 11.0 mg, 32%). MS (ESI) [M+H⁺]⁺=382.2.

Example 68 Synthesis of3-[4-methoxy-3-(2,2,2-trifluoro-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridineP-1626

Compound P-1626 was synthesized in three steps from3-hydroxy-4-methoxy-benzaldehyde 560 as shown in Scheme 52.

Step 1—Preparation of 4-Methoxy-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde(562)

3-Hydroxy-4-methoxy-benzaldehyde (560, 2.9 g, 19.5 mmol),2-iodo-1,1,1-trifluoroethane (561, 2.2 mL, 23 mmol), and potassiumcarbonate (3.7 g, 27 mmol) were dissolved in N,N-dimethylformamide (100mL). The solution was stirred at 90° C. overnight under an atmosphere ofnitrogen. The reaction was poured into water, extracted with ethylacetate, and washed with brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The compound wasisolated by silica gel column chromatography eluting with 25% to 50%ethyl acetate in hexanes to give white powder (562, 1.6 g, 40%).

Step 2—Preparation of3-Methoxy-[4-methoxy-3-(2,2,2-trifluoro-ethoxy)-phenyl]-methyl-1H-pyrrolo[2,3-b]pyridine(563)

1H-Pyrrolo[2,3-b]pyridine (0.2 g, 1.8 mmol),4-methoxy-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (562, 0.4 g, 1.9 mmol)and potassium hydroxide (0.5 g, 9.6 mmol) were combined in methanol (20mL). The reaction was heated to 50° C. under an atmosphere of nitrogenand stirred for two days. The reaction was poured into water, extractedwith ethyl acetate, and washed with brine. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated. The compoundwas isolated by silica gel column chromatography eluting with 40% to 75%ethyl acetate in hexanes to give orange oil (563, 0.2 g, 31%). MS (ESI)[M+H⁺]⁺=367.2 [M−H⁺]⁻=365.1.

Step 3—Preparation of3-[4-Methoxy-3-(2,2,2-trifluoro-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine(P-1626)

3-methoxy-[4-methoxy-3-(2,2,2-trifluoro-ethoxy)-phenyl]-methyl-1H-pyrrolo[2,3-b]pyridine(563) was reacted using the same protocol described in Example 28,Scheme 51, Step 3. The compound P-1626 was isolated by silica gel columnchromatography eluting with 50% to 75% ethyl acetate in hexanes. MS(ESI) [M+H⁺]⁺=337.1.

Example 69 Synthesis of N-phenyl-1H-pyrrolo[2,3-b]pyridin-3-amine P-0221

Compound P-0221 was synthesized in two or three steps from1H-pyrrolo[2,3-b]pyridine 94 as shown in Scheme 54.

Step 1—Preparation of 3-bromo-1-pyrrolo[2,3-b]pyridine (582)

To 1H-pyrrolo[2,3-b]pyridine (94, 600 mg) dissolved in 10 mL of 100%acetic acid was added the brominating agent DMAP-Br₃ (1.001 equiv.). Thereaction was heated at 75° C. until the orange color was gone and aprecipitate formed (about 60 min). It was dissolved with 50 mL of water(ppt dissolved) and adjusted to pH 8 with NaHCO₃ (aq. sat'd). Thecompound precipitated from the solution and was collected. The aqueousfraction was extracted with 3×30 mL with ethyl acetate. The combinedorganics were dried over Na₂SO₄, evaporated and the solids combined withthe previously collected solid (582, 87%).

Route A: Step 2 3-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(583)

To 3-bromo-1H-pyrrolo[2,3-b]pyridine (582, 0.5 mmol) dissolved in 5 mLof dry dioxane was added BEMP (2.5 equiv). The TIPS-OTf (2.0 equiv) wasthen added and the reaction was stirred overnight (15 hours). Thesolution was diluted with 20 mL of ethyl acetate and washed with 5%acetic acid (2×10 mL), water (2×10 mL), and brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered, evaporated and dried undervacuum. This material was used without further purification.

Route A: Step 3—Preparation of N-phenyl-1H-pyrrolo[2,3-b]pyridin-3-amine(P-0221)

A 1 dram vial was charged with aniline (2-3 equiv), and 10 mg of3-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 583 in 0.4 mLtoluene (dry, degassed). A catalyst stock solution containing 3 mmolPd(OAc)₂, 3 mmol biphenyl-2-yl-di-tert-butyl-phosphane and 15 mL oftoluene was prepared. To the reaction mixture, 0.050 mL of the catalystsolution was added. Excess NaOtBu was added as a solid to the reaction.The vial was then placed in a 75° C. oven for 60 minutes (shaken severaltimes over an hour). After cooling, the reaction was neutralized with0.100 mL of TFA. After 30 minutes the sample was evaporated andre-solvated in 0.300 mL of DMSO. The desired compound was isolated bypreparative HPLC/MS.

Rout B: Step 2—Preparation of N-phenyl-1H-pyrrolo[2,3-b]pyridin-3-amine(P-0221)

To 10 mg of 3-bromo-1H-pyrrolo[2,3-b]pyridine 582 was added 0.4 mL ofsulfolane and aniline (2-3 equiv). The vial was sealed and heated at180° C. for 10 minutes. After cooling, the desired compound was isolatedby preparative HPLC/MS.

The following compounds were prepared by one of the procedures describedin scheme 54, substituting aniline with a suitable amine in Step 5:

-   Methyl-phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1434),-   4-[Methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amino]-benzoic acid    (P-1435),-   (4-Chloro-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1436),-   Methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-m-tolyl-amine (P-1437),-   (4-Methoxy-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1438),-   (3-Chloro-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1439),-   (4-Fluoro-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1440),-   Methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-(4-trifluoromethoxy-phenyl)-amine    (P-1441),-   (2,4-Difluoro-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1442),-   (3-Fluoro-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1443),-   (4-Methoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1488),-   (3-Chloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1489),-   (3-Methoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1490),-   (4-Chloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1491),-   (1H-Pyrrolo[2,3-b]pyridin-3-yl)-(4-trifluoromethoxy-phenyl)-amine    (P-1492),-   (1H-Pyrrolo[2,3-b]pyridin-3-yl)-(3-trifluoromethoxy-phenyl)-amine    (P-1493),-   (3,4-Dichloro-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1494),-   (4-Phenoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1495),-   (3-Phenoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1496),-   (3-Benzyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1497),-   N-[3-(1H-Pyrrolo[2,3-b]pyridin-3-ylamino)-phenyl]-methanesulfonamide    (P-1498),-   3-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-3-ylamino)-phenol (P-1499),-   3-(1H-Pyrrolo[2,3-b]pyridin-3-ylamino)-benzenesulfonamide (P-1500),-   (2-Phenoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1501),-   (3,5-Dichloro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1502),-   (3,5-Dimethoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1503),-   [3-(4-Methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1504),-   (2-Benzyloxy-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine (P-1505),    and-   (3-Methoxy-phenyl)-methyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-amine    (P-1506).    The following table indicates the amine (Column 2) that is    substituted in place of the aniline in Route B, Step 2, or Route A,    Step 3, to afford the compounds (Column 3). Column 1 provides the    compound number and Column 4 the observed mass

Com- MS (ESI) pound [M + H⁺]⁺ number Amine Compound structure observedP-1434

224.3 P-1435

268.3 P-1436

258.3 P-1437

237.9 P-1438

254.3 P-1439

258.3 P-1440

242.3 P-1441

308.3 P-1442

260.3 P-1443

242.3 P-1488

239.9 P-1489

244.3 P-1490

240.3 P-1491

244.3 P-1492

293.9 P-1493

293.9 P-1494

291.9 P-1495

302.3 P-1496

302.3 P-1497

300.3 P-1498

303.1 P-1499

244.3 P-1500

289.1 P-1501

302.3 P-1502

277.9 P-1503

270.3 P-1504

291.1 P-1505

316.3 P-1506

254.3

Example 70 Synthesis of 4-chloro-7-azaindole 119

4-chloro-7-azaindole 119 was synthesized in two steps from 7-azaindoleaccording to the protocol of Scheme 81.

Step-1—Synthesis of 1H-Pyrrolo[2,3-b]pyridine 7-oxide (658)

1H-Pyrrolo[2,3-b]pyridine 7-oxide 658 was synthesized by reacting7-azaindole 94 with an oxidizing agent (e.g. m-CPBA) in a non-reactivesolvent (e.g. dimethoxyethane) as described by Schneller, S. W.: Luo,Jiann-Kuan. J. Org. Chem. 1980, 45:4045-4048. The compound was isolatedby filtration of the resulting solid that forms upon standing at 5° C.for typically 1-3 h.

Step-2—Synthesis of 4-chloro-7-azaindole (119)

4-chloro-7-azaindole 119 was synthesized by reacting1H-Pyrrolo[2,3-b]pyridine 7-oxide 658 with a chlorinating agent (e.g.POCl₃) neat as described by Schneller, S. W.; Luo, Jiann-Kuan. J. Org.Chem. 1980, 45:4045-4048. The resulting solution after heating for 3-5 hat elevated temperatures (100-150° C.) was neutralized with a base (e.g.NH₄OH) until a solid precipitated. The solid was isolated by filtration.

Example 71 Synthesis of[3-(4-Chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-2086 and3-[3-(4-Chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridineP-2085

Compounds P-2086 and P-2085 were synthesized in three steps fromcompounds 659 and 1H-pyrrolo[2,3-b]pyridine 94 as shown in Scheme 82.

Step 1—Preparation of3-(4-Chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-benzaldehyde (660)

To a solution of 3-(4-Chloro-2-fluoro-benzyloxy)-2-hydroxy-benzaldehyde(659, 140 mg, 0.5 mmol, prepared by protocol of Example 43, Steps 1 and2 of Scheme 71, using 4-chloro-2-fluoro-benzyl bromide in place of4-chloro-benzyl bromide in Step 1) in tetrahydrofuran (8 mL) was addeddropwise a mixture of 2-fluoro-ethanol (64 mg, 1.0 mmol),triphenylphosphine (180 mg, 0.7 mmol), and diisopropyl azodicarboxylate(120 mg, 0.6 mol) in tetrahydrofuran (5 ml) at 0° C. The reactionmixture was stirred at 0° C. for 10 minutes and then at 40° C. for 3days. The reaction mixture was dissolved in water and ethyl acetate. Theorganic layers were collected, washed with brine, and dried overmagnesium sulfate. After removal of solvent, the residue was purified bysilica gel column chromatography eluting with ethyl acetate in hexanesto provide the compound as a white solid (660, 88 mg, 54%). MS (ESI)[M+H⁺]⁺=327.12.

Step 2—Preparation of[3-(4-Chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(661) and3-{[3-(4-Chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-phenyl]-methoxy-methyl}-1H-pyrrolo[2,3-b]pyridine(662)

A solution of3-(4-chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-benzaldehyde (660,88 mg, 0.27 mmol), 1H-pyrrolo[2,3-b]pyridine (94, 38 mg, 0.32 mmol), andpotassium hydroxide (45 mg, 0.81 mol) in methanol (5 mL) was stirred atroom temperature for 24 hours. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was collected,washed with brine, and dried over sodium sulfate. After removal ofsolvent, the residue was purified by silica gel column chromatographyeluting with ethyl acetate in hexane to provide compound 661 as a whitesolid (67 mg, 56%), MS (ESI) [M+H⁺]⁺=445.13 and compound 662 as a whitesolid (36 mg, 29%), MS (ESI) [M+H⁺]⁺=459.15.

Step 3a—Preparation of[3-(4-Chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-2086)

To a solution of[3-(4-chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(661, 60 mg, 0.1 mmol) in tetrahydrofuran (10 mL) was added Dess-Martinperiodinane (69 mg, 0.16 mmol) at 0° C. The reaction mixture was stirredat room temperature for 3 hours. The reaction was quenched with asaturated solution of sodium thiosulfate, extracted with ethyl acetate,washed with sodium bicarbonate, brine, and dried over magnesium sulfate.After removal of solvent, the residue was purified by silica gel columnchromatography eluting with ethyl acetate in hexanes to provide thecompound as a white solid (P-2086, 15 mg, 20%). MS (ESI) [M+⁺]⁺=441.06.

Step 3b—Preparation of3-[3-(4-Chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine(P-2085)

A mixture of3-{[3-(4-chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-phenyl]-methoxy-methyl}-1H-pyrrolo[2,3-b]pyridine(662, 36 mg, 0.078 mmol), triethylsilane (0.5 mL, 3 mmol), andtrifluoroacetic acid (0.2 mL, 2 mmol) in acetonitrile (20 mL) wasstirred at 80° C. for 2 hours. The mixture was concentrated and theresidue was dissolved in ethyl acetate. The solution was washed withsaturated sodium bicarbonate, brine, and dried over sodium sulfate.After removal of solvent, the residue was purified by silica gel columnchromatography eluting with ethyl acetate in hexanes to provide thecompound as a yellow solid (P-2085, 24 mg, 71%). MS (ESI)[M+H⁺]⁺=429.15.

3-(4-Chloro-benzyloxy)-2-(2,2-difluoro-ethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-2075)

was prepared following the protocol of Scheme 82, substituting2-fluoro-ethanol with 2,2-difluoro-ethanol and substituting3-(4-Chloro-2-fluoro-benzyloxy)-2-hydroxy-benzaldehyde with3-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde (628 of Example 43) inStep 1 to provide P-2075. MS (ESI) [M+H⁺]⁺=443.1.

Example 72 Synthesis of[3-(2-Chloro-4-methanesulfonyl-benzyloxy)-2-ethoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-2094

Compound P-2094 was synthesized in four steps from compounds 635 and 663as shown in Scheme 83.

Step 1—Preparation of(3-Benzyloxy-2-ethoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(664)

To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(635, 1.306 g, 3.26 mmol) in tetrahydrofuran (42 mL) at −20° C. undernitrogen was added isopropylmagnesium chloride (1.70 mL, 2.0 M solutionin tetrahydrofuran, 3.40 mmol). The reaction mixture was stirred at −20°C. for 1.5 hours. It was allowed to warm to 5° C. and then kept at 5° C.for 1 hour. The reaction mixture was then cooled down to −20° C. To thissolution was slowly added a solution of 2-ethoxy-3-benzyloxybenzaldehyde(663, 0.698 g, 2.72 mmol, prepared by protocol of Example 43, Steps 1-3of Scheme 71, using benzyl bromide in place of 4-chloro-benzyl bromidein Step 1) in tetrahydrofuran (42 mL). The reaction mixture was stirredat −20° C. for 2.5 hrs, and was allowed to warm to 5° C. for 2.5 hours.The reaction mixture was poured into iced water, extracted with ethylacetate, washed with saturated ammonium chloride and brine, and driedover magnesium sulfate. After removal of solvent, the residue waspurified by silica gel column chromatography eluting with ethyl acetatein hexane to provide the compound as light-yellow oil (664, 200 mg,13.9%).

Step 2—Preparation of(2-ethoxy-3-hydroxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(665)

To a solution of(3-benzyloxy-2-ethoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(664,195 mg, 0.37 mmol) in a mixture of methanol (20 mL) andtetrahydrofuran (50 mL) was added palladium on carbon (50 mg, 10% wt.,0.2 mmol). The mixture was stirred under hydrogenation for seventeenhours. After removal of solvent, the residue was washed with a mixtureof ethyl ether and hexanes to provide the compound as a white solid(665, 63 mg, 95%). MS (ESI) [M+H⁺]⁺=439.37.

Step 3—Preparation of[3-(2-Chloro-4-methanesulfonyl-benzyloxy)-2-ethoxy-phenyl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(666)

To a solution of(2-ethoxy-3-hydroxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(665, 40 mg, 0.064 mmol) in tetrahydrofuran (15 mL) was added sodiumhydride (3.32 mg, 0.083 mmol) at room temperature under an atmosphere ofnitrogen. The mixture was stirred at room temperature for 40 minutes,then 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (21.72 mg, 0.077mmol) was added to the reaction mixture. It was stirred at roomtemperature overnight. The mixture was then poured into water and wasextracted with ethyl acetate. The organic layer was collected and washedwith brine, dried over magnesium sulfate. After removal of the solvent,a crude compound as light yellow oil was obtained (666, 84 mg).

Step 4—Preparation of[3-(2-Chloro-4-methanesulfonyl-benzyloxy)-2-ethoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-2094)

To a solution of(2-ethoxy-3-hydroxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(666, 84 mg, 0.054 mmol) in methanol (10 mL) was added potassiumhydroxide (6 N solution) until pH of the solution turned to over 10.Potassium fluoride (30 mg, 0.5 mmol) was then added to the reactionmixture and the mixture was stirred at room temperature for 6 hours. Thereaction mixture was then poured into saturated sodium carbonate and wasextracted with ethyl acetate. The organic layer was collected and washedwith brine, dried over magnesium sulfate. After removal of the solvent,the residue was purified by preparative HPLC to provide as a white solid(P-2094, 5 mg, 19%). MS (ESI) [M+H⁺]⁺=485.17.

Example 73 Synthesis of Propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amideP-1403

Compound P-1403 was synthesized in seven steps from3-fluoro-5-nitrobenzoic acid 667 as shown in Scheme 84.

Step 1—Preparation of 3-fluoro-5-aminobenzoic acid (668)

Into a Parr pressure reactor were added 3-fluoro-5-nitrobenzoic acid(667, 5.0 g, 0.027 mol), methanol (50.0 mL), 20% Pd(OH)₂ on carbon (300mg). The reaction was shaken under an atmosphere of hydrogen at 50 psiovernight. The reaction was filtered through celite and was concentratedto dryness to provide a white solid (668, 4.0 g, 95.0%).

Step 2—Preparation of 2-Fluoro-5-(propane-1-sulfonylamino)-benzoic acid(669)

To 3-fluoro-5-aminobenzoic acid (668, 3.00 g, 0.0180 mol) in methylenechloride (204 mL) were added pyridine (41 mL, 0.50 mol) andpropane-1-sulfonyl chloride (2.23 mL, 0.0198 mol) under an atmosphere ofnitrogen. The reaction was stirred at room temperature for 5 days. Thereaction was poured into water, adjusted pH to 1 with 1N HCl, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 5% methanol inmethylene chloride to give a white solid (669, 2.0 g, 42%). MS (ESI)[M−H⁺]⁺=260.1.

Step 3—Preparation of 2-Fluoro-5-(propane-1-sulfonylamino)-benzoic acidmethyl ester (670)

To 2-Fluoro-5-(propane-1-sulfonylamino)-benzoic acid (669, 2.0 g, 0.0076mol) in methanol (20.0 mL) was added sulfuric acid (0.90 mL, 0.017 mol).The reaction was stirred at room temperature overnight. The reaction wasconcentrated and purified with silica gel column chromatograph elutingwith 20% ethyl acetate in hexane to give a white solid (670, 1.27 g,62%). MS (ESI) [M−H⁺]⁻=274.1.

Step 4—Preparation of Propane-1 sulfonic acid (4fluoro-3-hydroxymethyl-phenyl)-amide (671)

To 2-Fluoro-5-(propane-1-sulfonylamino)-benzoic acid methyl ester (670,1.20 g, 0.00436 mol) in tetrahydrofuran (100.0 mL) was added lithiumtetrahydroaluminate (1.00 M in tetrahydrofuran, 10.0 mL) under anatmosphere of nitrogen. The reaction was stirred at room temperatureovernight. To the reaction was added Na₂SO₄.10H₂O (5 g), and thenstirred at room temperature for 1 hour. The reaction was filtered,concentrated and purified with silica gel column chromatography elutingwith 50% ethyl acetate in hexane to give the compound (671, 0.90 g,83%). MS (ESI) [M−H⁺]⁻=246.1.

Step 5—Preparation of Propane-1-sulfonic acid(4-fluoro-3-formyl-phenyl)-amide (672)

To propane-1-sulfonic acid (4-fluoro-3-hydroxymethyl-phenyl)-amide (671,0.483 g, 0.00195 mol) in tetrahydrofuran (10.0 mL), cooled withice/water, was added Dess-Martin periodinane (1.00 g, 0.00236 mol). Thereaction was stirred at room temperature for 10 minutes. The reactionwas poured into water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated and purified by silica gel column chromatographyeluting with 30% ethyl acetate in hexane to give a white solid (672, 360mg, 75%). MS (ESI) [M−H⁺]⁻=244.1.

Step 6—Preparation of Propane-1-sulfonic acid3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-fluoro-phenyl-amide(673)

To 5-bromo-7-azaindole (67, 170.0 mg, 0.86 mmol) in methanol (7.0 mL)were added propane-1-sulfonic acid (4-fluoro-3-formyl-phenyl)-amide(672, 220.0 mg, 0.90 mmol) and potassium hydroxide (0.50 g, 0.0089 mol)under an atmosphere of nitrogen. The reaction was stirred at roomtemperature overnight. The reaction was poured into water, acidifiedwith 1N HCl to pH=5, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 10% methanol in methylene chloride to give the compound (673, 55.0mg, 14.0%). MS (ESI) [M+H⁺]⁺=442.1, 444.1.

Step 7—Preparation of Propane-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide(P-1403)

To propane-1-sulfonic acid3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-fluoro-phenyl-amide(673, 55.0 mg, 0.12 mmol) in tetrahydrofuran (8.0 mL) was addedDess-Martin periodinane (70.0 mg, 0.17 mmol). The reaction was stirredat room temperature for 5 minutes. The reaction was concentrated withsilica gel and purified with silica gel column chromatography elutingwith 25% ethyl acetate in hexane to give an off-white solid (P-1403,26.2 mg, 47%). MS (ESI) [M+H⁺]⁺=4379, 439.9.

Example 74 Additional Compounds

Additional compounds of the invention were synthesized following themethods of the Examples above or similar methods, or by methods known tothose of skill in the art, and are shown in the following Table 1.

TABLE 1 Additional compounds of the invention

P-0001

P-0002

P-0003

P-0005

P-0010

P-0011

P-0012

P-0013

P-0014

P-0015

P-0017

P-0018

P-0019

P-0020

P-0021

P-0022

P-0023

P-0025

P-0028

P-0029

P-0030

P-0031

P-0032

P-0033

P-0039

P-0040

P-0041

P-0043

P-0044

P-0045

P-0046

P-0047

P-0048

P-0049

P-0050

P-0051

P-0053

P-0054

P-0056

P-0057

P-0058

P-0059

P-0060

P-0061

P-0062

P-0063

P-0064

P-0069

P-0070

P-0071

P-0072

P-0073

P-0074

P-0075

P-0076

P-0077

P-0080

P-0081

P-0083

P-0084

P-0085

P-0086

P-0087

P-0089

P-0090

P-0091

P-0092

P-0093

P-0094

P-0096

P-0097

P-0098

P-0099

P-0100

P-0101

P-0103

P-0104

P-0105

P-0106

P-0107

P-0108

P-0109

P-0110

P-0111

P-0112

P-0113

P-0115

P-0116

P-0117

P-0118

P-0119

P-0120

P-0123

P-0124

P-0125

P-0127

P-0128

P-0129

P-0130

P-0131

P-0132

P-0133

P-0134

P-0135

P-0136

P-0137

P-0138

P-0139

P-0140

P-0141

P-0142

P-0143

P-0144

P-0145

P-0146

P-0147

P-0148

P-0149

P-0150

P-0151

P-0152

P-0153

P-0154

P-0155

P-0157

P-0158

P-0159

P-0160

P-0161

P-0163

P-0164

P-0166

P-0167

P-0168

P-0169

P-0171

P-0172

P-0174

P-0175

P-0176

P-0177

P-0178

P-0179

P-0181

P-0182

P-0183

P-0185

P-0186

P-0187

P-0189

P-0190

P-0191

P-0192

P-0193

P-0194

P-0195

P-0196

P-0197

P-0198

P-0199

P-0200

P-0201

P-0202

P-0203

P-0204

P-0205

P-0206

P-0207

P-0208

P-0209

P-0210

P-0211

P-0212

P-0213

P-0214

P-0215

P-0216

P-0217

P-0218

P-0219

P-0220

P-0222

P-0223

P-0224

P-0225

P-0226

P-0227

P-0229

P-0230

P-0231

P-0232

P-0233

P-0234

P-0235

P-0236

P-0237

P-0238

P-0239

P-0240

P-0241

P-0242

P-0243

P-0244

P-0245

P-0246

P-0247

P-0248

P-0249

P-0250

P-0251

P-0252

P-0253

P-0254

P-0255

P-0256

P-0258

P-0259

P-0260

P-0261

P-0263

P-0264

P-0266

P-0267

P-0268

P-0270

P-0271

P-0272

P-0273

P-0274

P-0275

P-0276

P-0277

P-0278

P-0279

P-0280

P-0281

P-0282

P-0283

P-0284

P-0285

P-0286

P-0287

P-0288

P-0289

P-0290

P-0291

P-0292

P-0293

P-0294

P-0295

P-0296

P-0300

P-0301

P-0303

P-0304

P-0305

P-0306

P-0307

P-0309

P-0310

P-0311

P-0312

P-0313

P-0314

P-0315

P-0316

P-0317

P-0319

P-0320

P-0321

P-0322

P-0323

P-0324

P-0325

P-0326

P-0327

P-0328

P-0329

P-0330

P-0331

P-0332

P-0334

P-0335

P-0336

P-0337

P-0338

P-0339

P-0340

P-0341

P-0342

P-0343

P-0344

P-0345

P-0346

P-0347

P-0348

P-0349

P-0350

P-0351

P-0352

P-0353

P-0354

P-0355

P-0357

P-0358

P-0359

P-0360

P-0361

P-0362

P-0363

P-0364

P-0365

P-0366

P-0367

P-0368

P-0369

P-0370

P-0371

P-0372

P-0373

P-0374

P-0375

P-0376

P-0377

P-0378

P-0379

P-0380

P-0381

P-0382

P-0384

P-0385

P-0386

P-0387

P-0388

P-0389

P-0390

P-0391

P-0392

P-0393

P-0394

P-0395

P-0397

P-0398

P-0399

P-0400

P-0401

P-0402

P-0403

P-0404

P-0405

P-0406

P-0407

P-0408

P-0410

P-0411

P-0412

P-0413

P-0414

P-0415

P-0416

P-0417

P-0418

P-0419

P-0420

P-0422

P-0423

P-0424

P-0425

P-0426

P-0427

P-0428

P-0429

P-0430

P-0431

P-0432

P-0433

P-0434

P-0435

P-0436

P-0437

P-0438

P-0439

P-0440

P-0441

P-0442

P-0443

P-0444

P-0445

P-0446

P-0447

P-0448

P-0449

P-0450

P-0451

P-0452

P-0453

P-0454

P-0455

P-0456

P-0457

P-0458

P-0459

P-0460

P-0461

P-0462

P-0463

P-0464

P-0465

P-0466

P-0467

P-0468

P-0469

P-0470

P-0471

P-0472

P-0473

P-0474

P-0475

P-0476

P-0477

P-0478

P-0479

P-0480

P-0481

P-0482

P-0483

P-0484

P-0485

P-0487

P-0488

P-0489

P-0490

P-0491

P-0492

P-0493

P-0494

P-0495

P-0496

P-0497

P-0498

P-0499

P-0500

P-0501

P-0502

P-0503

P-0504

P-0505

P-0506

P-0507

P-0508

P-0509

P-0510

P-0511

P-0512

P-0513

P-0514

P-0515

P-0516

P-0517

P-0518

P-0519

P-0520

P-0522

P-0523

P-0524

P-0525

P-0526

P-0527

P-0528

P-0529

P-0530

P-0531

P-0532

P-0533

P-0534

P-0535

P-0536

P-0537

P-0538

P-0539

P-0540

P-0541

P-0542

P-0543

P-0544

P-0545

P-0546

P-0547

P-0548

P-0549

P-0550

P-0551

P-0552

P-0553

P-0554

P-0555

P-0556

P-0557

P-0558

P-0559

P-0560

P-0561

P-0562

P-0563

P-0564

P-0565

P-0566

P-0567

P-0568

P-0569

P-0570

P-0571

P-0572

P-0573

P-0574

P-0575

P-0576

P-0577

P-0578

P-0579

P-0580

P-0581

P-0582

P-0583

P-0584

P-0585

P-0586

P-0587

P-0588

P-0589

P-0590

P-0591

P-0592

P-0593

P-0594

P-0595

P-0596

P-0597

P-0598

P-0599

P-0600

P-0601

P-0602

P-0603

P-0604

P-0605

P-0606

P-0607

P-0608

P-0609

P-0610

P-0611

P-0612

P-0613

P-0614

P-0615

P-0616

P-0617

P-0618

P-0619

P-0620

P-0621

P-0622

P-0623

P-0624

P-0625

P-0626

P-0627

P-0628

P-0629

P-0630

P-0631

P-0632

P-0633

P-0634

P-0635

P-0637

P-0638

P-0639

P-0640

P-0641

P-0642

P-0643

P-0644

P-0645

P-0646

P-0647

P-0648

P-0649

P-0650

P-0651

P-0652

P-0653

P-0654

P-0655

P-0656

P-0657

P-0658

P-0659

P-0660

P-0661

P-0662

P-0663

P-0664

P-0665

P-0666

P-0667

P-0668

P-0669

P-0670

P-0671

P-0672

P-0673

P-0674

P-0675

P-0676

P-0677

P-0678

P-0679

P-0680

P-0681

P-0682

P-0683

P-0684

P-0686

P-0687

P-0688

P-0689

P-0690

P-0691

P-0692

P-0693

P-0694

P-0695

P-0696

P-0697

P-0698

P-0699

P-0701

P-0702

P-0703

P-0704

P-0705

P-0706

P-0707

P-0708

P-0709

P-0710

P-0711

P-0712

P-0713

P-0714

P-0715

P-0717

P-0718

P-0719

P-0720

P-0722

P-0723

P-0724

P-0725

P-0726

P-0727

P-0729

P-0730

P-0731

P-0732

P-0733

P-0735

P-0736

P-0737

P-0738

P-0739

P-0740

P-0741

P-0742

P-0743

P-0747

P-0748

P-0749

P-0750

P-0751

P-0752

P-0754

P-0755

P-0756

P-0757

P-0758

P-0759

P-0760

P-0761

P-0762

P-0764

P-0765

P-0766

P-0767

P-0768

P-0769

P-0770

P-0771

P-0772

P-0775

P-0777

P-0779

P-0780

P-0781

P-0782

P-0783

P-0784

P-0785

P-0786

P-0787

P-0788

P-0789

P-0790

P-0791

P-0792

P-0793

P-0794

P-0795

P-0796

P-0797

P-0799

P-0800

P-0801

P-0802

P-0803

P-0804

P-0808

P-0809

P-0810

P-0812

P-0813

P-0814

P-0815

P-0816

P-0817

P-0819

P-0820

P-0821

P-0822

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P-0824

P-0825

P-0826

P-0827

P-0828

P-0829

P-0830

P-0831

P-0832

P-0833

P-0834

P-0835

P-0836

P-0838

P-0839

P-0840

P-0842

P-0843

P-0844

P-0845

P-0846

P-0847

P-0849

P-0851

P-0852

P-0854

P-0855

P-0856

P-0857

P-0858

P-0859

P-0861

P-0862

P-0863

P-0864

P-0865

P-0866

P-0869

P-0870

P-0871

P-0872

P-0873

P-0875

P-0878

P-0879

P-0880

P-0881

P-0882

P-0883

P-0884

P-0886

P-0887

P-0888

P-0890

P-0891

P-0892

P-0893

P-0895

P-0896

P-0899

P-0900

P-0901

P-0903

P-0905

P-0906

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P-0920

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P-0932

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P-0939

P-0940

P-0941

P-0942

P-0943

P-0945

P-0946

P-0948

P-0949

P-0951

P-0953

P-0957

P-0959

P-0960

P-0961

P-0962

P-0963

P-0965

P-0966

P-0967

P-0968

P-0969

P-0970

P-0972

P-0973

P-0975

P-0976

P-0977

P-0978

P-0979

P-0980

P-0981

P-0982

P-0985

P-0986

P-0987

P-0988

P-0989

P-0990

P-0992

P-0993

P-0994

P-0995

P-0996

P-0998

P-0999

P-1000

P-1001

P-1003

P-1005

P-1007

P-1008

P-1010

P-1011

P-1012

P-1014

P-1016

P-1017

P-1018

P-1019

P-1021

P-1022

P-1023

P-1024

P-1025

P-1026

P-1027

P-1029

P-1030

P-1031

P-1032

P-1033

P-1034

P-1035

P-1036

P-1037

P-1038

P-1039

P-1040

P-1041

P-1042

P-1043

P-1044

P-1045

P-1046

P-1047

P-1048

P-1049

P-1050

P-1051

P-1052

P-1053

P-1054

P-1055

P-1057

P-1058

P-1059

P-1060

P-1061

P-1062

P-1063

P-1064

P-1065

P-1066

P-1067

P-1068

P-1069

P-1070

P-1071

P-1072

P-1073

P-1074

P-1075

P-1076

P-1077

P-1078

P-1079

P-1080

P-1081

P-1082

P-1083

P-1084

P-1085

P-1086

P-1087

P-1088

P-1089

P-1091

P-1092

P-1093

P-1094

P-1095

P-1096

P-1097

P-1098

P-1099

P-1100

P-1101

P-1102

P-1103

P-1104

P-1105

P-1106

P-1107

P-1108

P-1109

P-1110

P-1111

P-1112

P-1113

P-1114

P-1115

P-1117

P-1118

P-1119

P-1120

P-1121

P-1122

P-1123

P-1124

P-1125

P-1126

P-1127

P-1128

P-1129

P-1130

P-1132

P-1133

P-1134

P-1135

P-1136

P-1137

P-1138

P-1139

P-1140

P-1141

P-1142

P-1143

P-1144

P-1145

P-1146

P-1147

P-1148

P-1149

P-1150

P-1151

P-1152

P-1153

P-1154

P-1155

P-1156

P-1157

P-1158

P-1159

P-1160

P-1161

P-1162

P-1163

P-1164

P-1165

P-1166

P-1167

P-1168

P-1169

P-1170

P-1171

P-1172

P-1173

P-1174

P-1175

P-1176

P-1177

P-1178

P-1179

P-1181

P-1182

P-1183

P-1184

P-1185

P-1186

P-1187

P-1188

P-1189

P-1190

P-1191

P-1192

P-1193

P-1194

P-1195

P-1196

P-1197

P-1198

P-1199

P-1200

P-1201

P-1202

P-1203

P-1204

P-1205

P-1206

P-1207

P-1208

P-1209

P-1210

P-1211

P-1212

P-1213

P-1214

P-1215

P-1216

P-1217

P-1218

P-1219

P-1220

P-1221

P-1222

P-1223

P-1224

P-1225

P-1226

P-1227

P-1228

P-1229

P-1230

P-1231

P-1232

P-1233

P-1234

P-1235

P-1236

P-1237

P-1238

P-1249

P-1272

P-1273

P-1274

P-1275

P-1276

P-1277

P-1278

P-1279

P-1280

P-1281

P-1282

P-1283

P-1284

P-1285

P-1286

P-1287

P-1288

P-1316

P-1319

P-1320

P-1321

P-1322

P-1337

P-1340

P-1341

P-1342

P-1345

P-1346

P-1347

P-1348

P-1349

P-1365

P-1366

P-1367

P-1368

P-1369

P-1370

P-1379

P-1380

P-1381

P-1382

P-1383

P-1384

P-1385

P-1396

P-1397

P-1398

P-1400

P-1401

P-1404

P-1431

P-1433

P-1444

P-1448

P-1451

P-1452

P-1457

P-1458

P-1459

P-1460

P-1461

P-1473

P-1476

P-1479

P-1480

P-1484

P-1485

P-1507

P-1508

P-1509

P-1510

P-1511

P-1512

P-1517

P-1518

P-1525

P-1533

P-1535

P-1536

P-1537

P-1539

P-1540

P-1543

P-1550

P-1555

P-1556

P-1557

P-1560

P-1561

P-1562

P-1563

P-1565

P-1573

P-1574

P-1577

P-1585

P-1588

P-1592

P-1593

P-1604

P-1607

P-1608

P-1609

P-1610

P-1614

P-1617

P-1619

P-1620

P-1623

P-1624

P-1628

P-1629

P-1631

P-1632

P-1633

P-1634

P-1635

P-1638

P-1639

P-1640

P-1641

P-1642

P-1643

P-1644

P-1645

P-1646

P-1647

P-1648

P-1649

P-1650

P-1651

P-1653

P-1655

P-1658

P-1659

P-1662

P-1663

P-1664

P-1665

P-1666

P-1667

P-1668

P-1669

P-1670

P-1671

P-1672

P-1673

P-1674

P-1675

P-1676

P-1677

P-1678

P-1679

P-1680

P-1681

P-1682

P-1683

P-1684

P-1685

P-1686

P-1688

P-1689

P-1690

P-1691

P-1692

P-1693

P-1694

P-1695

P-1696

P-1697

P-1699

P-1701

P-1743

P-1745

P-1784

P-1785

P-1786

P-1787

P-1788

P-1789

P-1790

P-1791

P-1805

P-1806

P-1807

P-1808

P-1809

P-1810

P-1811

P-1812

P-1813

P-1814

P-1815

P-1826

P-1829

P-1831

P-1832

P-1833

P-1834

P-1835

P-1836

P-1837

P-1838

P-1846

P-1847

P-1856

P-1863

P-1866

P-1883

P-1888

P-1889

P-1890

P-1898

P-1936

P-1971

P-1981

P-1985

P-1995

P-1999

P-2001

P-2007

P-2008

P-2009

P-2010

P-2017

P-2018

P-2019

P-2021

P-2023

P-2027

P-2028

P-2029

P-2030

P-2031

P-2032

P-2065

P-2066

P-2067

P-2068

P-2069

P-2070

P-2071

P-2072

P-2073

P-2074

P-2077

P-2078

P-2079

P-2080

P-2081

P-2082

P-2083

P-2084

P-2087

P-2088

P-2089

P-2090

P-2091

P-2092

P-2093

P-2095

P-2096

P-2097

P-2098

Example 75 Kinase Activity Assays

The effect of potential modulators of kinase activity can be measured ina variety of different assays known in the art. For example, directradiometric, indirect FRET or AlphaScreen assays may be used to assessthe level of phosphorylation of a substrate in the presence of testcompounds in order to determine the inhibitory affect of the compound onthe kinase. Invitrogen (Carlsbad, Calif.) uses a FRET based assay forBtk, EGFR, EphB2, Flt3, Irak4, Kdr, MAP2K1, MAPKAPK2, PDGFRB, PKC theta,Stk6 and Yes. For these assays, compounds of the invention were screenedby Invitrogen using Z′-Lyte™ kinase assay.

Briefly, the Invitrogen kinase assay involves use of a specific peptidesubstrate optimized for each kinase, containing a fluorophore at eachend that make up the FRET pair. The peptide sensitivity to proteolyticcleavage depends on phosphorylation of the peptide. Non-phosphorylatedpeptide is cleaved by a protease while peptide phosphorylated by thekinase is not cleaved. Cleavage of the peptide disrupts the FRET betweenthe donor (coumarin) and acceptor (fluorescein) fluorophores, resultingin an increase in the ratio of donor emission to acceptor emission. Theemission ratio of coumarin to fluorescein is used to assess the reactionprogress. The extent of phosphorylation is determined from the emissionratio, which is low when the kinase is active (phosphorylated peptide isnot cleaved, FRET pair connected) or higher for inhibited kinase(non-phosphorylated peptide is cleaved, FRET pair separated). Thus, theassay involves a kinase reaction in the presence of varyingconcentrations of a given compound, a development reaction with sitespecific protease, and detection of the fluorescent emission ratio ofcoumarin and fluorescein. The emission ratio as a function of compoundconcentration was used to determine the IC value. Reaction conditionsfor each kinase are determined to provide optimal reaction times,incubation temperature, kinase and ATP concentrations. Test samples aremade up in 1× kinase buffer (50 mM HEPES pH 7.5, 50 mM MgCl₂, 5 mM EGTA,0.05% BRIJ-35) and compound at desired concentration prepared in DMSOsuch that the final DMSO is 1%. Assay controls include 0%phosphorylation, which contains no ATP, 100% phosphorylation control,which consists of a synthetically phosphorylated peptide, and 0%inhibition control, which contains active kinase conditions withoutcompound. Typically, assay plates are prepared to 10 μl final volume persample, adding 2.5 μl of compound at 4× the desired concentration in 4%DMSO (serial dilution of compound provides concentration curve), 5 μl ofthe desired kinase mixed with Z′-LYTE™ peptide substrate (2× in 2×kinase buffer, final peptide at 2 μM), and 2.5 μl of 4×ATP solution. Allkinase except for MAP2K1 were at 10 μM ATP in the kinase reaction, whileMAP2K1 was at 100 μM. Samples are mixed and the kinase reaction isincubated 1 hour at room temperature, after which 5 μl of developmentsolution is added and mixed. After incubation for another 1 hour at roomtemperature, 5 μl of stop reagent is added to each sample and mixed. Thefluorescence signals are measured to determine the emission ratio.

AlphaScreen assay was used to screen additional kinases. The assay issimilarly dependent on the phosphorylation of a peptide substrate. Inthis assay, an antibody that recognizes phosphorylated substrate isbound to an acceptor bead. The peptide substrate is attached to biotin,which binds to a donor bead that contains streptavidin. Thusphosphorylated substrate is bound by antibody and streptavidin, bringingthe donor and acceptor beads into close proximity when kinase is notinhibited. The donor produces singlet oxygen which results in emissionfrom the acceptor when they are in close proximity. Conversely, whenkinase is inhibited, the donor and acceptor beads are not associated andthe emission from the acceptor is reduced. The fluorescence signal vs.compound concentration was used to determine the IC₅₀ values.

Genetic Engineering

For some of the kinase screens, preparation of the kinase was required.Plasmids encoding a selection of kinase enzymes were engineered usingcommon polymerase chain reaction (PCR) methods. The relevant DNAsequences and encoded protein sequences used in the assay are shown foreach (see below). Complementary DNA cloned from various human tissueswere purchased from Invitrogen, and these were used as substrates in thePCR reactions. Specific custom synthetic oligonucleotide primers(Invitrogen see below) were designed to initiate the PCR product, andalso to provide the appropriate restriction enzyme cleavage sites forligation with the plasmids. In selected cases additional pairs ofoligonucleotides (see below) were used to introduce mutations into thecoding sequence to alter the sequence for enzyme activation (BRAF), forremoving problematic surface Cys residues (FGFR1), or for disabling thecapacity to bind ATP (MEK1 substrate).

In the case of KIT, the entire sequence encoding the enzyme was madethrough a gene synthesis procedure, using custom syntheticoligonucleotides covering the entire coding sequence (Invitrogen).

The plasmids used for ligation with the kinase-encoding inserts werederivatives of either pET (Novagen) for expression using E. coli, orpFastBac (Invitrogen) for expression using baculovirus infection ofinsect cell cultures. In each of these cases the kinase was engineeredto include a Histidine tag for purification using metal affinitychromatography.

In some cases the kinase-encoding plasmids were engineered asbicistronic mRNA to co-express a second protein that modifies the kinaseprotein during its expression in the host cell. In the cases of Abl,FGFR1, Flt1, Kdr, Kit, Met, Ret, and Src protein tyrosine phosphatase 1B(PTP), was co-expressed for dephosphorylation of the phospho-Tyrosines.In the case of ERK2, an activated form of MEK1 (MEK1DD), wasco-expressed for phosphorylation and activation of the ERK2. In the caseof p38a, an activated form of MEK6 (MKK6) was co-expressed forphosphorylation and activation of the p38a. In the case of BRAF, thechaperone CDC37, was co-expressed for more efficient protein folding ofthe BRAF.

Plasmids encoding phosphorylation substrate proteins were expressed asN-terminal GST fusions and C-terminal biotinylation fusions, using pGEXvectors (Amersham) modified to include sequences encoding a C-terminalbiotinylation tag. These substrates include MEK1, a substrate for BRAF,and BAD, a substrate for Pim1.

Protein Expression in E. coli and Purification.

For protein expression, plasmids containing genes of interest weretransformed into E. coli strains BL21(DE3)RIL or pLyS (Invitrogen) andtransformants selected for growth on LB agar plates containingappropriate antibiotics. Single colonies were grown overnight at 37° C.in 200 ml TB (Terrific broth) media. 16x1L of fresh TB media in 2.8 Lflasks were inoculated with 10 ml of overnight culture and grown withconstant shaking at 37° C. Once cultures reached an absorbance of 1.0 at600 nm, IPTG was added and cultures were allowed to grow for a further12 to 18 hrs at temperatures ranging from 12-30° C. Cells were harvestedby centrifugation and pellets frozen at −80° C. until ready for lysis.

For protein Purification; frozen E. coli cell pellets were resuspendedin lysis buffer and lysed using standard mechanical methods. Solubleproteins were purified via poly-Histidine tags using immobilized metalaffinity purification IMAC. In the case of all kinases described hereall have been purified using a 3 step purification process utilizing;IMAC, size exclusion chromatography and ion exchange chromatography. Inmost cases the poly-Histidine tag was removed using Thrombin(Calbiochem).

In some cases the purification protocol required modifications in orderto stabilize soluble protein during purification and concentration. Inthe case of BRaf 5 mM MgCl₂ was required throughout purification. In thecase of Ret a combination of 1 mM ATP and 5 mM MgCl₂ was required duringcell lysis and throughout purification. In the case of Zap70a 5M excessof AMP-PCP over protein was required as well as 5 mM MgCl₂.

Baculovirus Expression Vector System

Virus Production:

The transfection of a monolayer of Spodoptera frugiperda (Sf9) cells wasperformed utilizing a bacmid containing the gene of interest andCellfectin (Invitrogen) transfection reagent in antibiotic-free,serum-free Grace's complete media (Invitrogen). After a five hourincubation, the transfection media was removed, and the monolayer wasfed with Grace's media containing 10% FBS and antibiotics. After a 72 to96 hr incubation, the cell supernatant containing the virus washarvested. The titer of the virus stock was then determined using abaculovirus titer kit (BD). The virus stock was then expanded using lowMultiplicity of Infection (MOI of 0.1) cultures and harvested 48 hrspost-infection. The titer of the expanded virus stock was thendetermined for use in recombinant protein production.

Protein Production:

The protein expression level was optimized by varying the MOI (1-10) andtime of harvest (48-72 hrs). Sf9 cells were adapted to SF-900 IIserum-free media and grown in suspension in spinner flasks. The cellsuspension was then used to inoculate a Wave bioreactor for 25 Lproduction scale. Cells were harvested 48-72 hrs post-infection andstored at −80° C. until ready for lysis. Proteins were purifiedsimilarly to those expressed in E. coli.

Kinase Assay

AlphaScreen assays were done using compounds dissolved in DMSO to aconcentration of 20 mM. The compounds were diluted accordingly to thedesired final concentrations in each sample well, using 1:3 serialdilution for a total of 8 concentration points. Plates were preparedsuch that each kinase reaction is 20 μl in 1× kinase buffer, 5% DMSO and10 μM ATP. Kinase and assay conditions (defined below) used for eachkinase are shown in Table 3. After incubation of the kinase reaction for1 hour at room temperature, 5 μl of donor beads in stop buffer (50 mMEDTA in 1× kinase buffer) was added, the sample was mixed and incubatedfor 20 minutes at room temperature before adding 5 μl of acceptor beadsin stop buffer. The samples were incubated for 60 minutes at roomtemperature and the signal per well was read on AlphaQuest reader.Phosphorylated substrate results in binding of the antibody andassociation of the donor and acceptor beads such that signal correlateswith kinase activity. The signal vs. compound concentration was used todetermine the IC₅₀.

Assay Condition A:

Kinase buffer HEPES 50 mM, pH7.2, 5 mM MgCl₂, 5 mM MnCl₂, 0.2% BSA,0.01% NP-40 Substrate 100 nM biotin-(E4Y)3 (Open Source Biotech, Inc.)Donor bead 1 μg/ml Streptavidin coated bead (Perkin Elmer Life Science).Acceptor bead 1 μg/ml PY20 coated bead (Perkin Elmer Life Science)

Assay Condition B:

Kinase buffer 50 mM HEPES pH 7.0, 50 mM NaCl, 2 mM MgCl₂, 1 mM MnCl₂, 1mM DTT, 0.01% Tween-20. Substrate 100 nM biotin-MEK1 (prepared asdescribed above). Donor bead 10 μg/ml Streptavidin coated bead (PerkinElmer Life Science). Acceptor bead 10 μg/ml Protein A coated, bound toanti phospho MEK1/2 antibody (CellSignal)

Assay Condition C:

Kinase buffer 8 mM HEPES pH 7.0, 4 mM MgCl₂, 1 mM DTT, 0.01% Tween-20.Substrate 100 nM biotin-MBP (Upstate Biotechnology, Waltham, MA). Donorbead 10 μg/ml Streptavidin coated bead (Perkin Elmer Life Science).Acceptor bead 10 μg/ml Protein A coated, bound to anti phospho MBPantibody (CellSignal)

Assay Condition D:

Kinase 8 mM MOPS pH 7.4, 2 mM MgCl₂, 8 mM MnCl₂, 2 mM buffer DTT, 0.01%Tween-20. Substrate 30 nM biotin-(E4Y)10 (Upstate Biotechnology). Donorbead 20 μg/ml Streptavidin coated bead (Perkin Elmer Life Science).Acceptor 20 μg/ml PY20 antibody coated (Perkin Elmer Life bead Science)

Assay Condition E:

Kinase buffer 20 mM HEPES pH 7.0, 10 mM MgCl₂, 1 mM DTT, 0.01% Tween-20.Substrate 30 nM biotin-ATF2 (Upstate Biotechnology). Donor bead 10 μg/mlStreptavidin coated bead (Perkin Elmer Life Science). Acceptor bead 10μg/ml Protein A coated, bound to anti phospho ATF2 antibody (CellSignal)

Assay Condition F:

Kinase buffer 8 mM HEPES pH 7.0, 4 mM MgCl₂, 1 mM DTT, 0.01% Tween-20.Substrate 100 nM biotin-BAD (prepared as described above). Donor bead 10μg/ml Streptavidin coated bead (Perkin Elmer Life Science). Acceptorbead 10 μg/ml Protein A coated, bound to anti phospho BAD (Ser112)antibody (CellSignal)

Assay Condition G:

Kinase buffer MOPS 25 mM, pH7.1, 0.1 mM MgCl₂, 5 mM MnCl₂, 0.2% BSA, 1mM DTT, 0.01% Tween-20. Substrate 100 nM biotin-(E4Y)3 (Open SourceBiotech, Inc.) Donor bead 1 μg/ml Streptavidin coated bead (Perkin ElmerLife Science). Acceptor bead 1 μg/ml PY20 coated bead (Perkin Elmer LifeScience)

TABLE 3 Kinase reaction conditions (20 μl reaction volume) for kinasescreens. Plasmid Expression Kinase Vendor* Number Host Assay ConditionAbl P1121 E. coli A (1 ng kinase) B-Raf Upstate B (0.1 ng kinase) B-RafV600E P4254 Sf9 B (0.1 ng kinase) c-Raf-1 Upstate B (0.1 ng kinase) Erk2P4227 E. coli C (4 ng kinase) Fak P1358 Sf9 A (0.1 ng kinase) FGFR1P1351 E. coli A (0.1 ng kinase) Flt1 P1826 E. coli A (0.1 ng kinase)Flt4 ProQinase A (0.1 ng kinase) Fms Upstate D (0.5 ng kinase) Jnk1Upstate E (0.1 ng kinase) Jnk2 Roche E (0.05 ng kinase) Jnk3 Upstate E(0.1 ng kinase) Kit P1332 E. coli A (0.1 ng kinase) Met P1818 E. coli A(0.1 ng kinase) p38 P4292 E. coli E (6 ng kinase) Pim1 P1215 E. coli F(0.01 ng kinase) Pyk2 Upstate D (1 ng kinase) Ret P1378 E. coli A (0.01ng kinase) Src P1144 E. coli A (0.01 ng kinase) Zap70 P1868 Sf9 G (0.1ng kinase) *Upstate = Upstate Biotechnology Roche = Roche ProteinExpression Group (Indianapolis, IN) ProQinase = ProQinase GmbH(Freiburg, Germany)

Kit was alternatively purchased from Cell Signalling Technology. Kit andFms assays were also run at 100 μM ATP, where for Fms the 1× buffer was8 mM MOPS pH 7.0, 2 mM MgCl₂, 8 mM MnCl₂, 2 mM DTT, 50 mM NaC, 0.01% BSAand 0.01% Tween-20 and stop buffer was 8 mM MOPS, pH 7.0, 100 mM EDTA,0.01% BSA and for kit, 1 ng kinase was used and the 1× buffer was 8 mMMOPS pH 7.0, 1 mM MgCl₂, 2 mM MnC₂, 1 mM DTT, 0.001% BSA and 0.01%Tween-20, with substrate of 30 nM biotin-(E4Y)₁₀ (Upstate Biotechnology)and beads were at 10 g/ml in stop buffer of 8 mM MOPS, pH 7.0, 100 mMEDTA, 0.3% BSA.

Compounds screened by at least one of the methods described above, or bysimilar methods, having IC₅₀ of less than 10 μM are shown in tables 2a(Abl), 2b (B-Raf), 2c (B-Raf V600E), 2d (Btk), 2c (c-Raf-1), 2f (EGFR),2g (EphB2), 2h (Erk2), 21 (Fak), 2j (FGFR1), 2k (Flt1), 21 (Flt3), 2m(Flt4), 2n (Fms), 2o (Irak4), 2p (Jnk1), 2q (Jnk2), 2r (Jnk3), 2s (Kdr),2t (Kit), 2u (MAP2K1), 2v (MAPKAPK2), 2w (Met), 2x (p38), 2y (PDGFRB),2z (Pim1), 2aa (PKC theta), 2bb (Pyk2), 2 cc (Ret), 2dd (Src), 2ee(Stk6), and 2ff (Yes), 2gg (Zap70), 2hh (Akt3), 2ii (ALK), 2jj (Cdk2),2kk (Csk), 2ll (EphA2), 2 mm (EphB4), 2nn (Frk), 200 (Gskp3), 2 pp(Hek), 2qq (MAP4K4), 2rr (IGF1R), 2ss (1KK beta), 2tt (Itk), 2uu (Jak3),2vv (MLK1), 2ww (TrkA), 2xx (PDGFRA), 2yy (Plk1), 2zz (Brk), 2ab(ROCK1), 2ac (Syk), 2ad (TEC), and 2ac (Tie2).

TABLE 2a Compounds with activity toward kinase Abl with IC₅₀ ≦ 10 μM.Abl P-0001, P-0002, P-0003, P-0005, P-0007, P-0010, P-0011, P-0012,P-0019, P-0025, P-0028, P-0032, P-0033, P-0040, P-0041, P-0045, P-0047,P-0048, P-0050, P-0054, P-0056, P-0058, P-0068, P-0072, P-0074, P-0090,P-0093, P-0134, P-0140, P-0142, P-0167, P-0169, P-0196, P-0218, P-0224,P-0244, P-0316, P-0320, P-0448, P-0453, P-0501, P-0521, P-0529, P-0550,P-0559, P-0562, P-0579, P-0594, P-0599, P-0604, P-0611, P-0623, P-0624,P-0645, P-0656, P-0671, P-0675, P-0691, P-0693, P-0708, P-0738, P-0751,P-0762, P-0781, P-0794, P-0800, P-0806, P-0885, P-1011, P-1012, P-1115,P-1127, P-1318, P-1336, P-1394, P-1426

TABLE 2b Compounds with activity toward kinase B-Raf with IC₅₀ ≦ 10 μM.B-Raf P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007, P-0008,P-0009, P-0010, P-0016, P-0019, P-0021, P-0024, P-0025, P-0026, P-0027,P-0032, P-0034, P-0035, P-0036, P-0037, P-0038, P-0041, P-0042, P-0045,P-0050, P-0052, P-0054, P-0055, P-0056, P-0059, P-0060, P-0065, P-0066,P-0067, P-0068, P-0078, P-0079, P-0082, P-0088, P-0090, P-0093, P-0095,P-0102, P-0112, P-0114, P-0122, P-0126, P-0140, P-0143, P-0162, P-0165,P-0166, P-0171, P-0178, P-0180, P-0184, P-0188, P-0192, P-0196, P-0200,P-0210, P-0228, P-0257, P-0262, P-0265, P-0269, P-0271, P-0284, P-0293,P-0297, P-0302, P-0307, P-0310, P-0351, P-0356, P-0369, P-0382, P-0396,P-0414, P-0448, P-0486, P-0521, P-0550, P-0556, P-0559, P-0579, P-0594,P-0599, P-0604, P-0613, P-0636, P-0683, P-0685, P-0693, P-0697, P-0700,P-0716, P-0721, P-0728, P-0734, P-0744, P-0745, P-0746, P-0753, P-0763,P-0773, P-0774, P-0776, P-0778, P-0779, P-0794, P-0798, P-0805, P-0806,P-0807, P-0818, P-0837, P-0841, P-0842, P-0848, P-0850, P-0851, P-0853,P-0857, P-0860, P-0861, P-0863, P-0866, P-0867, P-0868, P-0874, P-0876,P-0877, P-0883, P-0885, P-0889, P-0894, P-0896, P-0897, P-0898, P-0902,P-0904, P-0907, P-0909, P-0910, P-0911, P-0912, P-0913, P-0919, P-0924,P-0928, P-0931, P-0932, P-0933, P-0937, P-0939, P-0941, P-0944, P-0946,P-0947, P-0952, P-0954, P-0955, P-0956, P-0958, P-0959, P-0973, P-0975,P-0978, P-0980, P-0983, P-0984, P-0987, P-0991, P-0997, P-0998, P-1003,P-1004, P-1006, P-1009, P-1013, P-1014, P-1020, P-1027, P-1028, P-1056,P-1076, P-1080, P-1110, P-1116, P-1243, P-1244, P-1246, P-1247, P-1249,P-1250, P-1251, P-1252, P-1253, P-1254, P-1255, P-1256, P-1257, P-1258,P-1259, P-1260, P-1261, P-1262, P-1263, P-1264, P-1265, P-1266, P-1267,P-1268, P-1269, P-1270, P-1279, P-1280, P-1281, P-1282, P-1288, P-1289,P-1317, P-1318, P-1336, P-1338, P-1341, P-1343, P-1346, P-1347, P-1348,P-1349, P-1365, P-1383, P-1384, P-1385, P-1386, P-1387, P-1388, P-1389,P-1390, P-1391, P-1395, P-1397, P-1419, P-1420, P-1429, P-1430, P-1431,P-1432, P-1433, P-1445, P-1446, P-1447, P-1451, P-1452, P-1453, P-1454,P-1455, P-1456, P-1457, P-1458, P-1459, P-1467, P-1469, P-1472, P-1473,P-1475, P-1477, P-1479, P-1480, P-1481, P-1485, P-1486, P-1526, P-1527,P-1528, P-1529, P-1532, P-1534, P-1539, P-1541, P-1542, P-1544, P-1546,P-1547, P-1548, P-1549, P-1552, P-1553, P-1554, P-1555, P-1556, P-1559,P-1566, P-1567, P-1568, P-1569, P-1570, P-1576, P-1577, P-1580, P-1581,P-1582, P-1583, P-1584, P-1585, P-1586, P-1589, P-1590, P-1591, P-1592,P-1593, P-1596, P-1597, P-1598, P-1599, P-1600, P-1602, P-1605, P-1608,P-1609, P-1610, P-1612, P-1613, P-1616, P-1621, P-1627, P-1630, P-1631,P-1636, P-1637, P-1638, P-1639, P-1656, P-1660, P-1663, P-1664, P-1665,P-1670, P-1671, P-1687, P-1700, P-1701, P-1702, P-1703, P-1704, P-1705,P-1706, P-1707, P-1708, P-1709, P-1710, P-1711, P-1712, P-1713, P-1714,P-1715, P-1716, P-1717, P-1718, P-1719, P-1720, P-1721, P-1722, P-1723,P-1724, P-1725, P-1726, P-1727, P-1728, P-1729, P-1730, P-1731, P-1732,P-1733, P-1734, P-1735, P-1736, P-1737, P-1738, P-1739, P-1740, P-1741,P-1742, P-1746, P-1747, P-1748, P-1749, P-1750, P-1751, P-1752, P-1753,P-1755, P-1756, P-1757, P-1758, P-1759, P-1760, P-1762, P-1763, P-1764,P-1765, P-1766, P-1767, P-1768, P-1769, P-1770, P-1771, P-1772, P-1773,P-1774, P-1775, P-1776, P-1777, P-1778, P-1779, P-1780, P-1781, P-1782,P-1783, P-1784, P-1798, P-1799, P-1800, P-1802, P-1804, P-1816, P-1817,P-1818, P-1819, P-1822, P-1823, P-1825, P-1827, P-1828, P-1839, P-1840,P-1841, P-1842, P-1864, P-1865, P-1871, P-1872, P-1873, P-1878, P-1879,P-1881, P-1882, P-1907, P-1912, P-1916, P-1980, P-1996, P-1997, P-1998,P-2005, P-2006, P-2007, P-2012, P-2013

TABLE 2c Compounds with activity toward kinase B-Raf V600E with IC₅₀ ≦10 μM. B-Raf P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007,P-0008, P-0009, P-0010, V600E P-0011, P-0012, P-0013, P-0014, P-0015,P-0016, P-0017, P-0019, P-0021, P-0022, P-0024, P-0025, P-0026, P-0027,P-0028, P-0032, P-0033, P-0034, P-0035, P-0036, P-0037, P-0038, P-0039,P-0040, P-0041, P-0042, P-0043, P-0044, P-0045, P-0046, P-0047, P-0048,P-0049, P-0050, P-0051, P-0052, P-0053, P-0054, P-0055, P-0056, P-0059,P-0060, P-0062, P-0063, P-0066, P-0067, P-0068, P-0070, P-0071, P-0072,P-0073, P-0074, P-0075, P-0078, P-0079, P-0082, P-0085, P-0088, P-0089,P-0090, P-0092, P-0093, P-0095, P-0097, P-0099, P-0100, P-0102, P-0107,P-0108, P-0109, P-0110, P-0112, P-0114, P-0118, P-0119, P-0121, P-0122,P-0124, P-0126, P-0129, P-0134, P-0135, P-0137, P-0139, P-0140, P-0141,P-0146, P-0147, P-0148, P-0152, P-0153, P-0156, P-0160, P-0162, P-0165,P-0166, P-0170, P-0171, P-0174, P-0175, P-0178, P-0180, P-0181, P-0184,P-0185, P-0186, P-0187, P-0188, P-0191, P-0192, P-0196, P-0199, P-0200,P-0205, P-0208, P-0210, P-0211, P-0215, P-0228, P-0231, P-0237, P-0242,P-0243, P-0244, P-0246, P-0248, P-0252, P-0255, P-0257, P-0261, P-0262,P-0265, P-0269, P-0271, P-0274, P-0284, P-0287, P-0293, P-0295, P-0297,P-0302, P-0307, P-0308, P-0311, P-0318, P-0320, P-0325, P-0333, P-0344,P-0347, P-0351, P-0352, P-0355, P-0356, P-0358, P-0369, P-0373, P-0381,P-0382, P-0386, P-0388, P-0396, P-0409, P-0414, P-0418, P-0420, P-0421,P-0434, P-0441, P-0447, P-0448, P-0453, P-0472, P-0483, P-0486, P-0493,P-0515, P-0521, P-0535, P-0550, P-0552, P-0559, P-0573, P-0579, P-0592,P-0594, P-0599, P-0600, P-0603, P-0604, P-0613, P-0623, P-0624, P-0636,P-0638, P-0645, P-0646, P-0647, P-0651, P-0656, P-0668, P-0671, P-0679,P-0683, P-0685, P-0691, P-0693, P-0696, P-0698, P-0700, P-0710, P-0713,P-0716, P-0721, P-0728, P-0730, P-0734, P-0744, P-0745, P-0746, P-0751,P-0753, P-0762, P-0763, P-0771, P-0773, P-0774, P-0776, P-0777, P-0778,P-0779, P-0794, P-0798, P-0803, P-0805, P-0806, P-0807, P-0810, P-0811,P-0816, P-0818, P-0819, P-0833, P-0837, P-0841, P-0842, P-0848, P-0850,P-0851, P-0853, P-0857, P-0860, P-0861, P-0863, P-0866, P-0867, P-0868,P-0874, P-0876, P-0877, P-0885, P-0886, P-0889, P-0893, P-0894, P-0896,P-0897, P-0898, P-0902, P-0904, P-0905, P-0907, P-0910, P-0911, P-0912,P-0913, P-0919, P-0927, P-0928, P-0931, P-0933, P-0937, P-0939, P-0944,P-0946, P-0947, P-0950, P-0951, P-0952, P-0954, P-0955, P-0956, P-0957,P-0958, P-0959, P-0962, P-0964, P-0971, P-0976, P-0980, P-0981, P-0983,P-0984, P-0991, P-0997, P-0998, P-1000, P-1002, P-1003, P-1004, P-1006,P-1007, P-1008, P-1009, P-1010, P-1013, P-1014, P-1015, P-1016, P-1018,P-1020, P-1021, P-1022, P-1024, P-1025, P-1026, P-1028, P-1029, P-1030,P-1031, P-1035, P-1043, P-1049, P-1056, P-1061, P-1063, P-1064, P-1065,P-1067, P-1069, P-1070, P-1071, P-1074, P-1082, P-1085, P-1090, P-1091,P-1112, P-1113, P-1116, P-1117, P-1120, P-1123, P-1128, P-1131, P-1138,P-1139, P-1140, P-1160, P-1177, P-1179, P-1180, P-1181, P-1183, P-1187,P-1194, P-1195, P-1199, P-1243, P-1244, P-1246, P-1247, P-1249, P-1250,P-1251, P-1252, P-1253, P-1254, P-1255, P-1256, P-1257, P-1258, P-1259,P-1260, P-1261, P-1262, P-1263, P-1264, P-1265, P-1266, P-1267, P-1269,P-1270, P-1279, P-1280, P-1281, P-1282, P-1283, P-1288, P-1289, P-1316,P-1317, P-1318, P-1323, P-1329, P-1336, P-1341, P-1343, P-1345, P-1346,P-1347, P-1348, P-1349, P-1365, P-1366, P-1368, P-1369, P-1370, P-1381,P-1383, P-1384, P-1385, P-1386, P-1387, P-1388, P-1389, P-1390, P-1391,P-1392, P-1394, P-1395, P-1396, P-1397, P-1398, P-1399, P-1402, P-1403,P-1409, P-1411, P-1413, P-1414, P-1415, P-1416, P-1417, P-1418, P-1419,P-1420, P-1423, P-1425, P-1426, P-1429, P-1430, P-1431, P-1432, P-1433,P-1444, P-1445, P-1446, P-1447, P-1448, P-1449, P-1450, P-1451, P-1452,P-1453, P-1454, P-1455, P-1456, P-1457, P-1458, P-1459, P-1462, P-1465,P-1466, P-1467, P-1469, P-1470, P-1471, P-1472, P-1473, P-1474, P-1475,P-1477, P-1478, P-1479, P-1480, P-1481, P-1485, P-1486, P-1495, P-1505,P-1506, P-1516, P-1526, P-1527, P-1528, P-1529, P-1530, P-1531, P-1532,P-1534, P-1539, P-1540, P-1541, P-1542, P-1544, P-1545, P-1546, P-1547,P-1548, P-1549, P-1550, P-1552, P-1553, P-1554, P-1556, P-1558, P-1559,P-1561, P-1564, P-1566, P-1567, P-1568, P-1569, P-1570, P-1572, P-1575,P-1576, P-1577, P-1578, P-1579, P-1581, P-1582, P-1583, P-1584, P-1585,P-1586, P-1589, P-1590, P-1591, P-1592, P-1594, P-1596, P-1597, P-1598,P-1599, P-1600, P-1601, P-1602, P-1605, P-1606, P-1607, P-1608, P-1609,P-1610, P-1611, P-1612, P-1613, P-1614, P-1621, P-1627, P-1630, P-1631,P-1636, P-1637, P-1638, P-1639, P-1656, P-1660, P-1663, P-1664, P-1665,P-1666, P-1670, P-1671, P-1687, P-1698, P-1700, P-1701, P-1702, P-1703,P-1704, P-1705, P-1706, P-1707, P-1708, P-1709, P-1710, P-1711, P-1712,P-1713, P-1714, P-1715, P-1716, P-1717, P-1718, P-1719, P-1720, P-1721,P-1722, P-1723, P-1724, P-1725, P-1726, P-1727, P-1728, P-1729, P-1730,P-1731, P-1732, P-1733, P-1734, P-1735, P-1736, P-1737, P-1738, P-1739,P-1740, P-1741, P-1742, P-1746, P-1747, P-1748, P-1749, P-1750, P-1751,P-1752, P-1753, P-1755, P-1756, P-1757, P-1758, P-1759, P-1760, P-1762,P-1763, P-1764, P-1765, P-1766, P-1767, P-1768, P-1769, P-1770, P-1771,P-1772, P-1773, P-1774, P-1775, P-1776, P-1777, P-1778, P-1779, P-1780,P-1781, P-1782, P-1783, P-1784, P-1797, P-1798, P-1799, P-1800, P-1802,P-1804, P-1816, P-1817, P-1818, P-1819, P-1822, P-1823, P-1828, P-1839,P-1840, P-1841, P-1842, P-1843, P-1864, P-1865, P-1871, P-1872, P-1873,P-1878, P-1879, P-1881, P-1882, P-1907, P-1912, P-1916, P-1980, P-1996,P-1997, P-1998, P-2005, P-2006, P-2007, P-2012, P-2013

TABLE 2d Compounds with activity toward kinase Btk with IC₅₀ ≦ 10 μM.Btk: P-0005, P-0006, P-0007, P-0009, P-0010, P-0011, P-0012, P-0013,P-0014, P-0015, P-0016, P-0017, P-0019, P-0020, P-0021, P-0022, P-0024,P-0025, P-0026, P-0027, P-0028, P-0029, P-0031, P-0033, P-0040, P-0041,P-0042, P-0043, P-0044, P-0045, P-0046, P-0047, P-0048, P-0049, P-0050,P-0051, P-0052, P-0053, P-0054, P-0055, P-0059, P-0060, P-0061, P-0062,P-0063, P-0067, P-0068, P-0070, P-0072, P-0073, P-0074, P-0075, P-0079,P-0081, P-0082, P-0083, P-0085, P-0088, P-0089, P-0090, P-0093, P-0094,P-0097, P-0102, P-0107, P-0108, P-0109, P-0112, P-0113, P-0125, P-0134,P-0135, P-0138, P-0139, P-0145, P-0148, P-0152, P-0156, P-0166, P-0171,P-0217, P-0228, P-0257, P-0280, P-0297, P-0302, P-0304, P-0314, P-0321,P-0325, P-0351, P-0418, P-0429, P-0763, P-0806, P-0807, P-0885, P-0897,P-0991, P-0997, P-1020, P-1262, P-1266, P-1267, P-1269, P-1317, P-1336,P-1343, P-1346, P-1388, P-1389, P-1390, P-1420, P-1426, P-1459, P-1473,P-1475, P-1479, P-1480, P-1481, P-1485, P-1486

TABLE 2e Compounds with activity toward kinase c-Raf-1 with IC₅₀ ≦ 10 μMc-Raf-1: P-0001, P-0002, P-0004, P-0005, P-0006, P-0007, P-0008, P-0009,P-0010, P-0015, P-0016, P-0021, P-0024, P-0025, P-0026, P-0027, P-0032,P-0034, P-0035, P-0036, P-0037, P-0038, P-0042, P-0045, P-0052, P-0055,P-0066, P-0078, P-0079, P-0082, P-0088, P-0090, P-0102, P-0112, P-0114,P-0121, P-0122, P-0137, P-0156, P-0162, P-0165, P-0166, P-0170, P-0178,P-0180, P-0184, P-0188, P-0210, P-0228, P-0257, P-0262, P-0265, P-0269,P-0297, P-0302, P-0307, P-0356, P-0369, P-0382, P-0396, P-0418, P-0486,P-0521, P-0535, P-0542, P-0559, P-0604, P-0613, P-0636, P-0656, P-0685,P-0700, P-0716, P-0721, P-0728, P-0734, P-0744, P-0745, P-0746, P-0753,P-0763, P-0773, P-0774, P-0776, P-0778, P-0779, P-0794, P-0798, P-0805,P-0806, P-0807, P-0811, P-0818, P-0837, P-0841, P-0842, P-0848, P-0850,P-0851, P-0853, P-0857, P-0860, P-0861, P-0863, P-0866, P-0867, P-0868,P-0874, P-0876, P-0877, P-0883, P-0885, P-0889, P-0890, P-0894, P-0896,P-0897, P-0898, P-0902, P-0904, P-0907, P-0909, P-0910, P-0911, P-0912,P-0913, P-0919, P-0924, P-0928, P-0931, P-0933, P-0937, P-0939, P-0941,P-0944, P-0946, P-0947, P-0950, P-0952, P-0954, P-0955, P-0956, P-0957,P-0958, P-0959, P-0964, P-0971, P-0973, P-0974, P-0975, P-0978, P-0983,P-0987, P-0991, P-0997, P-0998, P-1002, P-1003, P-1004, P-1006, P-1009,P-1013, P-1014, P-1015, P-1017, P-1020, P-1027, P-1028, P-1047, P-1056,P-1061, P-1063, P-1064, P-1065, P-1070, P-1071, P-1076, P-1077, P-1078,P-1079, P-1118, P-1122, P-1145, P-1243, P-1244, P-1246, P-1247, P-1249,P-1250, P-1251, P-1253, P-1254, P-1255, P-1256, P-1257, P-1258, P-1260,P-1261, P-1262, P-1265, P-1279, P-1283, P-1288, P-1289, P-1316, P-1317,P-1318, P-1336, P-1338, P-1365, P-1386, P-1387, P-1388, P-1389, P-1390,P-1391, P-1395, P-1396, P-1397, P-1398, P-1403, P-1413, P-1419, P-1431,P-1432, P-1433, P-1448, P-1451, P-1452, P-1453, P-1454, P-1455, P-1456,P-1458, P-1541, P-1542, P-1546, P-1547, P-1581, P-1583, P-1630, P-1671,P-1712, P-1713, P-1714, P-1733, P-1737, P-1738, P-1739, P-1740, P-1783,P-1839, P-1864, P-1871, P-1873, P-1878, P-1879, P-1881, P-1882

TABLE 2f Compounds with activity toward kinase EGFR with IC₅₀ ≦ 10 μMEGFR: P-0001, P-0002, P-0003, P-0004, P-0025, P-0095, P-0153, P-0877

TABLE 2g Compounds with activity toward kinase EphB2 with IC₅₀ ≦ 10 μMEphB2: P-0001, P-0003, P-0005, P-0006, P-0007, P-0009, P-0010, P-0011,P-0012, P-0013, P-0014, P-0015, P-0016, P-0017, P-0019, P-0020, P-0021,P-0022, P-0025, P-0027, P-0028, P-0029, P-0032, P-0033, P-0034, P-0035,P-0036, P-0038, P-0040, P-0041, P-0042, P-0043, P-0044, P-0045, P-0048,P-0050, P-0052, P-0053, P-0055, P-0056, P-0059, P-0062, P-0067, P-0068,P-0070, P-0072, P-0074, P-0075, P-0078, P-0083, P-0088, P-0090, P-0093,P-0102, P-0107, P-0109, P-0114, P-0124, P-0125, P-0126, P-0139, P-0145,P-0186

TABLE 2h Compounds with activity toward kinase Erk2 with IC₅₀ ≦ 10 μMErk2: P-0031, P-0041, P-0058, P-0154, P-0550, P-0611, P-1336

TABLE 2i Compounds with activity toward kinase Fak with IC₅₀ ≦ 10 μMFak: P-0001, P-0002, P-0003, P-0004, P-0006, P-0007, P-0008, P-0009,P-0016, P-0018, P-0024, P-0025, P-0026, P-0027, P-0032, P-0034, P-0035,P-0036, P-0037, P-0045, P-0054, P-0055, P-0067, P-0078, P-0088, P-0102,P-0112, P-0114, P-0166, P-0196, P-0209, P-0210, P-0211, P-0224, P-0257,P-0269, P-0276, P-0293, P-0298, P-0302, P-0310, P-0333, P-0391, P-0396,P-0437, P-0486, P-0494, P-0501, P-0611, P-0668, P-0675, P-0685, P-0691,P-0700, P-0721, P-0774, P-0795, P-0797, P-0806, P-0811, P-0818, P-0837,P-0850, P-0851, P-0867, P-0885, P-0889, P-0910, P-0911, P-0933, P-0951,P-0955, P-0956, P-0986, P-0992, P-1002, P-1009, P-1013, P-1020, P-1054,P-1083, P-1114, P-1146, P-1190, P-1247, P-1249, P-1250, P-1253, P-1255,P-1256, P-1263, P-1264, P-1266, P-1267, P-1269, P-1279, P-1280, P-1281,P-1282, P-1288, P-1289, P-1316, P-1318, P-1321, P-1323, P-1329, P-1336,P-1341, P-1346, P-1347, P-1348, P-1349, P-1359, P-1365, P-1383, P-1384,P-1385, P-1387, P-1388, P-1389, P-1390, P-1391, P-1392, P-1394, P-1396,P-1397, P-1400, P-1401, P-1402, P-1403, P-1411, P-1431, P-1432, P-1433,P-1445, P-1446, P-1447, P-1449, P-1450, P-1451, P-1452, P-1453, P-1455,P-1456, P-1457, P-1458, P-1459, P-1473, P-1474, P-1475, P-1477, P-1478,P-1479, P-1480, P-1481, P-1482, P-1485, P-1486, P-1492, P-1495, P-1500,P-1502, P-1685

TABLE 2j Compounds with activity toward kinase FGFR with IC₅₀ ≦ 10 μMFGFR: P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007, P-0008,P-0009, P-0010, P-0011, P-0012, P-0013, P-0015, P-0016, P-0017, P-0019,P-0020, P-0021, P-0024, P-0025, P-0026, P-0027, P-0028, P-0029, P-0032,P-0033, P-0034, P-0035, P-0036, P-0037, P-0038, P-0039, P-0040, P-0041,P-0042, P-0043, P-0045, P-0050, P-0052, P-0054, P-0055, P-0056, P-0058,P-0059, P-0066, P-0067, P-0068, P-0072, P-0073, P-0078, P-0079, P-0082,P-0088, P-0089, P-0090, P-0093, P-0096, P-0097, P-0099, P-0101, P-0102,P-0103, P-0112, P-0114, P-0119, P-0121, P-0129, P-0132, P-0134, P-0137,P-0140, P-0142, P-0149, P-0150, P-0152, P-0156, P-0158, P-0165, P-0166,P-0167, P-0168, P-0170, P-0171, P-0175, P-0178, P-0180, P-0184, P-0189,P-0192, P-0196, P-0198, P-0204, P-0205, P-0206, P-0210, P-0211, P-0215,P-0217, P-0218, P-0219, P-0220, P-0227, P-0228, P-0232, P-0233, P-0239,P-0242, P-0244, P-0246, P-0248, P-0257, P-0262, P-0265, P-0267, P-0269,P-0271, P-0274, P-0284, P-0287, P-0289, P-0293, P-0294, P-0297, P-0298,P-0302, P-0304, P-0308, P-0309, P-0316, P-0320, P-0321, P-0325, P-0326,P-0329, P-0335, P-0339, P-0341, P-0344, P-0346, P-0351, P-0363, P-0368,P-0369, P-0371, P-0373, P-0374, P-0379, P-0383, P-0385, P-0391, P-0392,P-0396, P-0400, P-0404, P-0409, P-0411, P-0418, P-0420, P-0421, P-0424,P-0426, P-0442, P-0447, P-0448, P-0452, P-0453, P-0459, P-0473, P-0474,P-0479, P-0483, P-0486, P-0489, P-0493, P-0495, P-0501, P-0507, P-0510,P-0515, P-0520, P-0521, P-0535, P-0550, P-0556, P-0559, P-0561, P-0562,P-0563, P-0575, P-0579, P-0594, P-0599, P-0611, P-0613, P-0615, P-0623,P-0624, P-0632, P-0636, P-0640, P-0645, P-0647, P-0656, P-0658, P-0668,P-0671, P-0679, P-0683, P-0685, P-0691, P-0693, P-0697, P-0698, P-0699,P-0700, P-0708, P-0710, P-0721, P-0728, P-0730, P-0734, P-0737, P-0744,P-0745, P-0746, P-0749, P-0751, P-0753, P-0763, P-0771, P-0773, P-0774,P-0776, P-0798, P-0805, P-0806, P-0807, P-0811, P-0818, P-0819, P-0826,P-0828, P-0835, P-0837, P-0841, P-0848, P-0850, P-0851, P-0853, P-0854,P-0857, P-0860, P-0865, P-0867, P-0868, P-0874, P-0876, P-0877, P-0885,P-0889, P-0894, P-0896, P-0897, P-0898, P-0902, P-0904, P-0907, P-0910,P-0911, P-0912, P-0913, P-0919, P-0927, P-0933, P-0935, P-0937, P-0944,P-0947, P-0950, P-0951, P-0952, P-0954, P-0955, P-0956, P-0958, P-0964,P-0974, P-0976, P-0977, P-0979, P-0983, P-0991, P-0997, P-1002, P-1004,P-1008, P-1009, P-1015, P-1017, P-1018, P-1020, P-1021, P-1027, P-1066,P-1074, P-1078, P-1110, P-1111, P-1116, P-1120, P-1123, P-1125, P-1142,P-1181, P-1182, P-1188, P-1194, P-1246, P-1249, P-1250, P-1251, P-1252,P-1253, P-1254, P-1255, P-1256, P-1257, P-1258, P-1259, P-1260, P-1261,P-1262, P-1263, P-1264, P-1265, P-1266, P-1267, P-1269, P-1270, P-1272,P-1273, P-1274, P-1279, P-1280, P-1281, P-1282, P-1283, P-1287, P-1288,P-1289, P-1316, P-1317, P-1318, P-1321, P-1322, P-1323, P-1325, P-1326,P-1327, P-1328, P-1329, P-1330, P-1331, P-1332, P-1333, P-1334, P-1335,P-1336, P-1337, P-1338, P-1339, P-1340, P-1341, P-1342, P-1343, P-1344,P-1345, P-1346, P-1347, P-1348, P-1349, P-1365, P-1366, P-1367, P-1369,P-1377, P-1380, P-1381, P-1382, P-1383, P-1384, P-1385, P-1386, P-1387,P-1388, P-1389, P-1390, P-1391, P-1392, P-1393, P-1394, P-1395, P-1396,P-1397, P-1398, P-1399, P-1402, P-1403, P-1404, P-1406, P-1407, P-1409,P-1411, P-1415, P-1416, P-1418, P-1419, P-1420, P-1423, P-1424, P-1426,P-1428, P-1429, P-1430, P-1431, P-1433, P-1445, P-1446, P-1447, P-1448,P-1451, P-1452, P-1453, P-1454, P-1455, P-1456, P-1458, P-1459, P-1460,P-1461, P-1463, P-1464, P-1465, P-1467, P-1468, P-1469, P-1472, P-1473,P-1474, P-1475, P-1476, P-1477, P-1478, P-1479, P-1480, P-1481, P-1482,P-1485, P-1486, P-1512, P-1516, P-1522, P-1524, P-1525, P-1526, P-1527,P-1528, P-1529, P-1530, P-1534, P-1538, P-1539, P-1542, P-1545, P-1546,P-1547, P-1548, P-1549, P-1550, P-1554, P-1555, P-1556, P-1561, P-1564,P-1577, P-1581, P-1582, P-1583, P-1584, P-1585, P-1589, P-1591, P-1592,P-1593, P-1595, P-1597, P-1603, P-1605, P-1608, P-1609, P-1610, P-1614,P-1621, P-1622, P-1624, P-1625, P-1685

TABLE 2k Compounds with activity toward kinase Flt1 with IC₅₀ ≦ 10 μMFlt1: P-0001, P-0002, P-0003, P-0004, P-0005, P-0008, P-0009, P-0011,P-0012, P-0013, P-0016, P-0017, P-0018, P-0019, P-0020, P-0021, P-0024,P-0026, P-0027, P-0032, P-0033, P-0034, P-0036, P-0037, P-0038, P-0039,P-0041, P-0054, P-0055, P-0056, P-0067, P-0068, P-0072, P-0078, P-0082,P-0088, P-0090, P-0091, P-0101, P-0103, P-0112, P-0114, P-0127, P-0134,P-0150, P-0154, P-0166, P-0177, P-0180, P-0184, P-0194, P-0196, P-0206,P-0211, P-0214, P-0224, P-0244, P-0269, P-0274, P-0278, P-0287, P-0298,P-0302, P-0315, P-0320, P-0325, P-0326, P-0337, P-0371, P-0373, P-0383,P-0404, P-0409, P-0421, P-0448, P-0455, P-0461, P-0470, P-0477, P-0483,P-0486, P-0491, P-0514, P-0515, P-0521, P-0550, P-0559, P-0579, P-0603,P-0624, P-0629, P-0632, P-0636, P-0640, P-0656, P-0668, P-0679, P-0683,P-0685, P-0691, P-0700, P-0708, P-0721, P-0733, P-0737, P-0749, P-0751,P-0757, P-0768, P-0771, P-0773, P-0774, P-0777, P-0805, P-0866, P-0868,P-0951, P-0958, P-0962, P-1002, P-1008, P-1010, P-1018, P-1021, P-1027,P-1082, P-1110, P-1112, P-1147, P-1160, P-1181, P-1194, P-1246, P-1247,P-1250, P-1251, P-1255, P-1256, P-1259, P-1260, P-1261, P-1262, P-1266,P-1269, P-1279, P-1289, P-1317, P-1318, P-1365, P-1366, P-1370, P-1372,P-1373, P-1383, P-1393, P-1395, P-1403, P-1404, P-1406, P-1411, P-1415,P-1416, P-1417, P-1418, P-1420, P-1422, P-1423, P-1424, P-1425, P-1426,P-1427, P-1428, P-1429, P-1430, P-1431, P-1432, P-1433, P-1445, P-1446,P-1447, P-1457, P-1460, P-1461, P-1462, P-1463, P-1464, P-1465, P-1467,P-1468, P-1469, P-1472, P-1475, P-1486, P-1491, P-1492, P-1495, P-1497,P-1499, P-1502, P-1505, P-1523, P-1526, P-1527, P-1528, P-1529, P-1530,P-1531, P-1532, P-1533, P-1534, P-1541, P-1542, P-1544, P-1546, P-1547,P-1548, P-1549, P-1552, P-1553, P-1554, P-1556, P-1557, P-1559, P-1564,P-1566, P-1567, P-1569, P-1570, P-1571, P-1572, P-1575, P-1576, P-1577,P-1580, P-1581, P-1582, P-1583, P-1584, P-1585, P-1586, P-1587, P-1589,P-1590, P-1591, P-1592, P-1593, P-1594, P-1595, P-1596, P-1597, P-1598,P-1599, P-1600, P-1601, P-1602, P-1603, P-1605, P-1606, P-1608, P-1609,P-1610, P-1612, P-1613, P-1614, P-1615, P-1618, P-1619, P-1621, P-1622,P-1624, P-1625, P-1686

TABLE 2l Compounds with activity toward kinase Flt3 with IC₅₀ ≦ 10 μMFlt3: P-0088, P-0262, P-0409, P-0636, P-0806, P-1244, P-1280, P-1318,P-1336, P-1394, P-1426

TABLE 2m Compounds with activity toward kinase Flt4 with IC₅₀ ≦ 10 μMFlt4: P-0001, P-0003, P-0005, P-0011, P-0012, P-0019, P-0024, P-0029,P-0032, P-0039, P-0040, P-0041, P-0090, P-0093, P-0097, P-0117, P-0142,P-0167, P-0190, P-0196, P-0204, P-0205, P-0206, P-0211, P-0215, P-0218,P-0224, P-0265, P-0316, P-0325, P-0335, P-0352, P-0418, P-0448, P-0452,P-0453, P-0495, P-0521, P-0544, P-0550, P-0559, P-0579, P-0594, P-0599,P-0617, P-0624, P-0632, P-0645, P-0656, P-0668, P-0679, P-0691, P-0703,P-0708, P-0737, P-0738, P-0751, P-0762, P-0771, P-0813

TABLE 2n Compounds with activity toward kinase Fms with IC₅₀ ≦ 10 μMFms: P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007, P-0008,P-0009, P-0010, P-0012, P-0016, P-0019, P-0020, P-0021, P-0025, P-0026,P-0027, P-0032, P-0033, P-0034, P-0035, P-0036, P-0037, P-0038, P-0042,P-0045, P-0048, P-0054, P-0067, P-0068, P-0072, P-0078, P-0079, P-0082,P-0088, P-0090, P-0093, P-0101, P-0102, P-0103, P-0112, P-0114, P-0121,P-0129, P-0134, P-0145, P-0152, P-0166, P-0170, P-0175, P-0180, P-0184,P-0189, P-0196, P-0210, P-0211, P-0228, P-0233, P-0237, P-0239, P-0244,P-0257, P-0262, P-0269, P-0274, P-0284, P-0287, P-0291, P-0293, P-0297,P-0298, P-0302, P-0317, P-0325, P-0327, P-0333, P-0351, P-0369, P-0373,P-0383, P-0391, P-0396, P-0409, P-0418, P-0420, P-0421, P-0461, P-0483,P-0486, P-0491, P-0501, P-0515, P-0535, P-0559, P-0563, P-0613, P-0636,P-0656, P-0685, P-0721, P-0733, P-0753, P-0763, P-0771, P-0773, P-0774,P-0778, P-0798, P-0805, P-0806, P-0807, P-0811, P-0818, P-0835, P-0837,P-0848, P-0850, P-0851, P-0853, P-0854, P-0857, P-0867, P-0874, P-0876,P-0883, P-0885, P-0898, P-0911, P-0913, P-0919, P-0927, P-0931, P-0933,P-0952, P-0954, P-0955, P-0956, P-0958, P-1002, P-1008, P-1009, P-1013,P-1110, P-1112, P-1124, P-1194, P-1246, P-1247, P-1249, P-1250, P-1251,P-1252, P-1253, P-1255, P-1259, P-1260, P-1262, P-1263, P-1264, P-1265,P-1266, P-1267, P-1269, P-1279, P-1280, P-1281, P-1282, P-1289, P-1316,P-1317, P-1318, P-1321, P-1323, P-1324, P-1325, P-1326, P-1327, P-1328,P-1329, P-1330, P-1331, P-1332, P-1333, P-1334, P-1335, P-1336, P-1337,P-1338, P-1339, P-1340, P-1341, P-1342, P-1343, P-1344, P-1346, P-1365,P-1366, P-1368, P-1369, P-1370, P-1372, P-1376, P-1380, P-1381, P-1384,P-1385, P-1386, P-1387, P-1388, P-1389, P-1390, P-1391, P-1392, P-1393,P-1394, P-1395, P-1397, P-1399, P-1400, P-1402, P-1403, P-1404, P-1405,P-1406, P-1409, P-1410, P-1411, P-1415, P-1416, P-1419, P-1420, P-1421,P-1423, P-1425, P-1426, P-1427, P-1428, P-1429, P-1430, P-1431, P-1432,P-1433, P-1445, P-1447, P-1448, P-1449, P-1450, P-1451, P-1452, P-1453,P-1454, P-1455, P-1456, P-1457, P-1458, P-1459, P-1460, P-1461, P-1462,P-1463, P-1464, P-1465, P-1466, P-1467, P-1468, P-1469, P-1470, P-1471,P-1472, P-1473, P-1474, P-1475, P-1476, P-1477, P-1478, P-1479, P-1480,P-1481, P-1482, P-1483, P-1485, P-1486, P-1488, P-1489, P-1490, P-1491,P-1492, P-1493, P-1494, P-1495, P-1496, P-1497, P-1498, P-1499, P-1500,P-1501, P-1502, P-1503, P-1504, P-1505, P-1506, P-1511, P-1522, P-1525,P-1526, P-1527, P-1528, P-1529, P-1530, P-1532, P-1534, P-1541, P-1542,P-1544, P-1545, P-1546, P-1547, P-1548, P-1549, P-1552, P-1553, P-1554,P-1555, P-1556, P-1558, P-1559, P-1564, P-1566, P-1567, P-1568, P-1569,P-1570, P-1571, P-1572, P-1575, P-1576, P-1580, P-1581, P-1583, P-1586,P-1587, P-1589, P-1591, P-1594, P-1595, P-1596, P-1597, P-1598, P-1599,P-1602, P-1606, P-1608, P-1609, P-1610, P-1611, P-1612, P-1613, P-1615,P-1616, P-1618, P-1621, P-1625, P-1627, P-1630, P-1631, P-1636, P-1637,P-1638, P-1639, P-1652, P-1653, P-1654, P-1656, P-1657, P-1660, P-1663,P-1664, P-1665, P-1670, P-1671, P-1685, P-1687, P-1700, P-1701, P-1702,P-1703, P-1704, P-1705, P-1706, P-1707, P-1708, P-1709, P-1710, P-1711,P-1712, P-1713, P-1714, P-1715, P-1716, P-1717, P-1718, P-1719, P-1720,P-1721, P-1722, P-1723, P-1724, P-1725, P-1726, P-1727, P-1728, P-1729,P-1730, P-1731, P-1732, P-1733, P-1734, P-1735, P-1736, P-1737, P-1738,P-1739, P-1740, P-1741, P-1742, P-1746, P-1747, P-1748, P-1749, P-1750,P-1751, P-1753, P-1754, P-1755, P-1756, P-1757, P-1758, P-1759, P-1760,P-1761, P-1762, P-1763, P-1764, P-1765, P-1766, P-1767, P-1768, P-1769,P-1771, P-1772, P-1773, P-1774, P-1775, P-1776, P-1778, P-1779, P-1780,P-1781, P-1782, P-1783, P-1784, P-1796, P-1798, P-1799, P-1800, P-1802,P-1803, P-1804, P-1816, P-1817, P-1818, P-1819, P-1821, P-1822, P-1827,P-1828, P-1839, P-1840, P-1864, P-1871, P-1872, P-1873, P-1878, P-1879,P-1881, P-1882, P-1907, P-1912, P-1916, P-1980, P-1996, P-1997, P-1998,P-2005, P-2006, P-2007, P-2012, P-2013

TABLE 2o Compounds with activity toward kinase Irak4 with IC₅₀ ≦ 10 μMIrak4: P-0002, P-0020, P-0076, P-0087, P-0091, P-0130

TABLE 2p Compounds with activity toward kinase Jnk1 with IC₅₀ ≦ 10 μMJnk1: P-0001, P-0002, P-0003, P-0004, P-0006, P-0008, P-0009, P-0010,P-0015, P-0016, P-0021, P-0025, P-0026, P-0027, P-0032, P-0033, P-0034,P-0035, P-0036, P-0037, P-0038, P-0040, P-0042, P-0045, P-0052, P-0054,P-0056, P-0066, P-0078, P-0079, P-0082, P-0088, P-0090, P-0102, P-0112,P-0114, P-0121, P-0134, P-0140, P-0156, P-0184, P-0196, P-0204, P-0228,P-0244, P-0257, P-0269, P-0285, P-0297, P-0302, P-0308, P-0431, P-0448,P-0486, P-0521, P-0559, P-0579, P-0599, P-0624, P-0636, P-0668, P-0685,P-0691, P-0700, P-0721, P-0728, P-0734, P-0745, P-0753, P-0763, P-0774,P-0807, P-0848, P-0850, P-0851, P-0853, P-0860, P-0876, P-0897, P-0956,P-0958, P-0991, P-0997, P-1002, P-1008, P-1009, P-1021, P-1251, P-1253,P-1256, P-1260, P-1262, P-1266, P-1279, P-1280, P-1281, P-1288, P-1289,P-1317, P-1318, P-1336, P-1338, P-1343, P-1346, P-1347, P-1348, P-1349,P-1356, P-1359, P-1365, P-1366, P-1370, P-1384, P-1385, P-1390, P-1394,P-1400, P-1402, P-1432, P-1433, P-1445, P-1446, P-1447, P-1456, P-1458,P-1459, P-1465, P-1468, P-1473, P-1475, P-1486, P-1523, P-1534, P-1546,P-1547, P-1548, P-1549, P-1553, P-1554, P-1556, P-1566, P-1567, P-1570,P-1576, P-1577, P-1585, P-1589, P-1591, P-1592, P-1596, P-1602, P-1610,P-1611, P-1618, P-1621, P-1627, P-1631, P-1636, P-1637, P-1638, P-1639,P-1656, P-1660, P-1687, P-1702, P-1706, P-1707, P-1708, P-1720, P-1722,P-1723, P-1724, P-1725, P-1727, P-1730, P-1731, P-1742, P-1748, P-1749,P-1750, P-1751, P-1755, P-1756, P-1757, P-1759, P-1760, P-1764, P-1765,P-1767, P-1770, P-1775, P-1776, P-1777, P-1778, P-1779, P-1827, P-1828,P-1839, P-1842, P-1864, P-1873, P-1878, P-1879, P-1896, P-1897, P-1898,P-2007

TABLE 2q Compounds with activity toward kinase Jnk2 with IC₅₀ ≦ 10 μMJnk2: P-0001, P-0005, P-0006, P-0009, P-0013, P-0015, P-0016, P-0025,P-0027, P-0033, P-0034, P-0035, P-0040, P-0042, P-0052, P-0054, P-0056,P-0066, P-0069, P-0079, P-0082, P-0088, P-0090, P-0121, P-0140, P-0142,P-0156, P-0184, P-0196, P-0204, P-0228, P-0238, P-0269, P-0285, P-0297,P-0308, P-0448, P-0486, P-0521, P-0579, P-0594, P-0599, P-0623, P-0685,P-0700, P-0721, P-0734, P-0744, P-0746, P-0774, P-1253, P-1318, P-1445,P-1447, P-1486, P-1547, P-1548, P-1554, P-1566, P-1567, P-1570, P-1575,P-1576, P-1589, P-1591, P-1602, P-1611, P-1621, P-1627, P-1656, P-1671,P-1687, P-1700, P-1702, P-1711, P-1720, P-1722, P-1723, P-1724, P-1727,P-1728, P-1729, P-1730, P-1731, P-1732, P-1737, P-1742, P-1748, P-1749,P-1750, P-1751, P-1753, P-1755, P-1756, P-1757, P-1759, P-1760, P-1764,P-1765, P-1767, P-1770, P-1776, P-1777, P-1778, P-1779, P-1827, P-1828,P-1864, P-2007

TABLE 2r Compounds with activity toward kinase Jnk3 with IC₅₀ ≦ 10 μMJnk3: P-0001, P-0002, P-0003, P-0004, P-0006, P-0008, P-0009, P-0010,P-0015, P-0016, P-0024, P-0025, P-0026, P-0027, P-0031, P-0032, P-0033,P-0034, P-0035, P-0036, P-0037, P-0038, P-0040, P-0041, P-0045, P-0047,P-0052, P-0054, P-0056, P-0058, P-0059, P-0066, P-0078, P-0079, P-0080,P-0088, P-0089, P-0090, P-0093, P-0102, P-0112, P-0114, P-0115, P-0117,P-0122, P-0132, P-0133, P-0134, P-0165, P-0166, P-0167, P-0176, P-0179,P-0184, P-0189, P-0190, P-0196, P-0204, P-0211, P-0213, P-0218, P-0228,P-0238, P-0244, P-0257, P-0263, P-0269, P-0279, P-0285, P-0300, P-0308,P-0313, P-0320, P-0371, P-0378, P-0448, P-0483, P-0521, P-0550, P-0559,P-0562, P-0579, P-0594, P-0599, P-0604, P-0624, P-0625, P-0632, P-0636,P-0640, P-0645, P-0656, P-0659, P-0668, P-0671, P-0675, P-0682, P-0683,P-0691, P-0697, P-0698, P-0703, P-0710, P-0716, P-0734, P-0738, P-0753,P-0755, P-0757, P-0763, P-0774, P-0778, P-0807, P-0822, P-0851, P-0951,P-0962, P-0991, P-1002, P-1005, P-1008, P-1010, P-1011, P-1016, P-1018,P-1021, P-1022, P-1032, P-1082, P-1087, P-1088, P-1253, P-1279, P-1280,P-1289, P-1317, P-1318, P-1346, P-1347, P-1348, P-1349, P-1355, P-1356,P-1359, P-1372, P-1375, P-1384, P-1385, P-1394, P-1400, P-1445, P-1447,P-1458, P-1465, P-1468, P-1473, P-1475, P-1477, P-1485, P-1486, P-1489,P-1490, P-1505, P-1529, P-1534, P-1546, P-1547, P-1548, P-1554, P-1561,P-1566, P-1567, P-1570, P-1576, P-1577, P-1585, P-1589, P-1591, P-1592,P-1610, P-1611, P-1618, P-1621, P-1636, P-1687, P-1702, P-1703, P-1704,P-1706, P-1707, P-1713, P-1716, P-1720, P-1722, P-1724, P-1742, P-1748,P-1749, P-1750, P-1753, P-1756, P-1757, P-1759, P-1764, P-1765, P-1767,P-1770, P-1775, P-1776, P-1777, P-1827, P-1828, P-1864, P-2007

TABLE 2s Compounds with activity toward kinase Kdr with IC₅₀ ≦ 10 μMKdr: P-0001, P-0003, P-0005, P-0006, P-0007, P-0009, P-0011, P-0012,P-0013, P-0014, P-0015, P-0016, P-0017, P-0018, P-0019, P-0020, P-0021,P-0022, P-0023, P-0024, P-0025, P-0027, P-0028, P-0029, P-0030, P-0031,P-0032, P-0033, P-0039, P-0040, P-0041, P-0042, P-0043, P-0044, P-0045,P-0046, P-0048, P-0049, P-0050, P-0051, P-0052, P-0053, P-0054, P-0055,P-0056, P-0057, P-0059, P-0060, P-0061, P-0063, P-0064, P-0065, P-0067,P-0068, P-0069, P-0070, P-0071, P-0073, P-0074, P-0075, P-0076, P-0077,P-0078, P-0080, P-0081, P-0082, P-0084, P-0085, P-0086, P-0087, P-0088,P-0089, P-0090, P-0091, P-0092, P-0093, P-0096, P-0097, P-0098, P-0100,P-0101, P-0102, P-0103, P-0105, P-0106, P-0107, P-0108, P-0110, P-0111,P-0112, P-0113, P-0114, P-0115, P-0117, P-0120, P-0122, P-0125, P-0126,P-0127, P-0128, P-0129, P-0130, P-0131, P-0133, P-0134, P-0135, P-0136,P-0137, P-0139, P-0140, P-0141, P-0142, P-0143, P-0144, P-0145, P-0147,P-0149, P-0152, P-0157, P-0158, P-0161, P-0162, P-0163, P-0164, P-0165,P-0167, P-0168, P-0169, P-0170, P-0172, P-0173, P-0174, P-0175, P-0176,P-0177, P-0179, P-0180, P-0182, P-0184, P-0189, P-0190, P-0192, P-0194,P-0195, P-0196, P-0197, P-0198, P-0199, P-0202, P-0203, P-0204, P-0206,P-0212, P-0213, P-0216, P-0218, P-0224, P-0225, P-0226, P-0230, P-0234,P-0242, P-0243, P-0260, P-0261, P-0262, P-0267, P-0268, P-0269, P-0270,P-0274, P-0279, P-0287, P-0288, P-0289, P-0293, P-0295, P-0296, P-0299,P-0308, P-0316, P-0319, P-0320, P-0321, P-0322, P-0326, P-0337, P-0339,P-0369, P-0376, P-0379, P-0391, P-0409, P-0418, P-0427, P-0448, P-0455,P-0458, P-0473, P-0482, P-0495, P-0521, P-0550, P-0559, P-0562, P-0579,P-0611, P-0623, P-0624, P-0632, P-0640, P-0645, P-0668, P-0679, P-0683,P-0691, P-0703, P-0708, P-0730, P-0737, P-0738, P-0751, P-0762, P-0771,P-0777, P-0796, P-0806, P-0813, P-0933, P-0951, P-0956, P-0962, P-0981,P-1023, P-1244, P-1280, P-1318, P-1394, P-1426

TABLE 2t Compounds with activity toward kinase Kit with IC₅₀ ≦ 10 μMKit: P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007, P-0008,P-0009, P-0011, P-0012, P-0013, P-0016, P-0017, P-0018, P-0019, P-0020,P-0021, P-0024, P-0026, P-0027, P-0028, P-0029, P-0030, P-0031, P-0032,P-0033, P-0034, P-0035, P-0036, P-0037, P-0038, P-0039, P-0040, P-0041,P-0042, P-0050, P-0054, P-0056, P-0059, P-0064, P-0067, P-0069, P-0072,P-0078, P-0079, P-0080, P-0082, P-0086, P-0088, P-0090, P-0093, P-0097,P-0101, P-0102, P-0103, P-0112, P-0114, P-0115, P-0117, P-0120, P-0121,P-0122, P-0123, P-0127, P-0129, P-0132, P-0133, P-0134, P-0136, P-0140,P-0142, P-0152, P-0154, P-0157, P-0166, P-0167, P-0168, P-0171, P-0175,P-0176, P-0179, P-0180, P-0184, P-0189, P-0190, P-0195, P-0196, P-0204,P-0205, P-0206, P-0210, P-0211, P-0213, P-0216, P-0217, P-0218, P-0224,P-0233, P-0235, P-0237, P-0244, P-0248, P-0253, P-0257, P-0262, P-0263,P-0265, P-0269, P-0274, P-0279, P-0284, P-0287, P-0289, P-0293, P-0298,P-0300, P-0302, P-0304, P-0315, P-0316, P-0321, P-0323, P-0325, P-0326,P-0333, P-0341, P-0346, P-0352, P-0367, P-0369, P-0371, P-0373, P-0378,P-0384, P-0385, P-0391, P-0392, P-0396, P-0402, P-0404, P-0409, P-0411,P-0418, P-0420, P-0421, P-0427, P-0447, P-0448, P-0450, P-0453, P-0459,P-0461, P-0473, P-0483, P-0491, P-0495, P-0499, P-0501, P-0511, P-0519,P-0521, P-0535, P-0550, P-0554, P-0556, P-0559, P-0561, P-0562, P-0563,P-0579, P-0594, P-0599, P-0604, P-0611, P-0613, P-0617, P-0623, P-0624,P-0625, P-0626, P-0632, P-0636, P-0640, P-0644, P-0645, P-0647, P-0656,P-0658, P-0659, P-0668, P-0671, P-0679, P-0682, P-0683, P-0685, P-0690,P-0691, P-0693, P-0697, P-0699, P-0700, P-0703, P-0708, P-0721, P-0733,P-0736, P-0737, P-0738, P-0749, P-0751, P-0753, P-0755, P-0757, P-0762,P-0763, P-0771, P-0773, P-0774, P-0776, P-0778, P-0794, P-0796, P-0798,P-0800, P-0806, P-0810, P-0813, P-0815, P-0818, P-0825, P-0835, P-0837,P-0848, P-0850, P-0851, P-0853, P-0854, P-0857, P-0860, P-0861, P-0865,P-0866, P-0867, P-0874, P-0876, P-0877, P-0885, P-0889, P-0898, P-0905,P-0907, P-0910, P-0911, P-0913, P-0919, P-0924, P-0927, P-0931, P-0933,P-0935, P-0937, P-0951, P-0952, P-0954, P-0955, P-0956, P-0958, P-0962,P-0964, P-0978, P-0983, P-1002, P-1008, P-1009, P-1010, P-1013, P-1016,P-1018, P-1021, P-1033, P-1082, P-1084, P-1096, P-1110, P-1112, P-1160,P-1181, P-1194, P-1246, P-1247, P-1249, P-1250, P-1251, P-1252, P-1253,P-1254, P-1255, P-1256, P-1257, P-1259, P-1260, P-1261, P-1262, P-1263,P-1264, P-1266, P-1267, P-1268, P-1269, P-1275, P-1279, P-1280, P-1281,P-1289, P-1316, P-1317, P-1318, P-1320, P-1321, P-1323, P-1329, P-1336,P-1338, P-1341, P-1343, P-1346, P-1347, P-1348, P-1349, P-1365, P-1366,P-1367, P-1368, P-1369, P-1370, P-1372, P-1376, P-1380, P-1382, P-1383,P-1384, P-1385, P-1386, P-1387, P-1388, P-1389, P-1390, P-1391, P-1392,P-1393, P-1394, P-1395, P-1396, P-1397, P-1399, P-1400, P-1402, P-1403,P-1404, P-1406, P-1407, P-1408, P-1409, P-1410, P-1411, P-1413, P-1414,P-1415, P-1416, P-1417, P-1419, P-1420, P-1422, P-1423, P-1424, P-1425,P-1426, P-1427, P-1428, P-1429, P-1430, P-1431, P-1432, P-1433, P-1445,P-1446, P-1447, P-1449, P-1450, P-1451, P-1452, P-1453, P-1454, P-1455,P-1456, P-1457, P-1458, P-1460, P-1461, P-1462, P-1463, P-1464, P-1465,P-1466, P-1467, P-1468, P-1469, P-1470, P-1471, P-1472, P-1474, P-1475,P-1476, P-1478, P-1479, P-1480, P-1481, P-1482, P-1483, P-1484, P-1486,P-1488, P-1489, P-1490, P-1493, P-1495, P-1497, P-1498, P-1499, P-1500,P-1501, P-1502, P-1503, P-1505, P-1506, P-1514, P-1521, P-1522, P-1525,P-1526, P-1527, P-1528, P-1529, P-1530, P-1531, P-1532, P-1534, P-1538,P-1541, P-1542, P-1543, P-1544, P-1545, P-1546, P-1547, P-1548, P-1549,P-1550, P-1551, P-1552, P-1553, P-1554, P-1557, P-1559, P-1562, P-1564,P-1565, P-1566, P-1567, P-1568, P-1569, P-1574, P-1575, P-1576, P-1578,P-1580, P-1581, P-1582, P-1583, P-1590, P-1591, P-1593, P-1598, P-1599,P-1605, P-1630, P-1671, P-1685, P-1700, P-1703, P-1704, P-1705, P-1706,P-1707, P-1708, P-1709, P-1711, P-1712, P-1713, P-1714, P-1718, P-1719,P-1720, P-1733, P-1737, P-1739, P-1740, P-1767, P-1776, P-1783, P-1798,P-1822, P-1839, P-1840, P-1864, P-1865, P-1871, P-1872, P-1873, P-1878,P-1879, P-1881, P-1882, P-1980, P-1996, P-1997, P-1998

TABLE 2u Compounds with activity toward kinase MAP2K1 with IC₅₀ ≦ 10 μMMAP2K1: P-0001, P-0002, P-0003, P-0005, P-0006, P-0008, P-0010, P-0011,P-0012, P-0014, P-0015, P-0017, P-0018, P-0022, P-0023, P-0029, P-0031,P-0041, P-0046, P-0051, P-0057, P-0058, P-0061, P-0076, P-0079, P-0081,P-0087, P-0098, P-0099, P-0105, P-0108, P-0111, P-0120, P-0149, P-0152,P-0158, P-0167, P-0170, P-0177, P-0194, P-0198, P-0331, P-0337, P-0568,P-0806

TABLE 2v Compounds with activity toward kinase MAPKAPK2 with IC₅₀ ≦ 10μM MAPKAPK2: P-0007, P-0041, P-0057, P-0058, P-0077, P-0086, P-0104,P-0106, P-0151, P-0226

TABLE 2w Compounds with activity toward kinase Met with IC₅₀ ≦ 10 μMMet: P-0001, P-0002, P-0004, P-0006, P-0008, P-0009, P-0015, P-0016,P-0020, P-0026, P-0027, P-0028, P-0034, P-0035, P-0037, P-0038, P-0041,P-0052, P-0054, P-0058, P-0066, P-0076, P-0078, P-0082, P-0101, P-0114,P-0117, P-0140, P-0146, P-0149, P-0156, P-0165, P-0184, P-0228, P-0262,P-0269, P-0320, P-0325, P-0369, P-0419, P-0542, P-0550, P-0675, P-0685,P-0700, P-0716, P-0721, P-0746, P-0761, P-0763, P-0773, P-0778, P-0781,P-0811, P-0822, P-0842, P-0951, P-0962, P-1008, P-1012, P-1023, P-1037,P-1068, P-1092, P-1114, P-1132, P-1280, P-1394, P-1465, P-1527

TABLE 2x Compounds with activity toward kinase p38 with IC₅₀ ≦ 10 μMp38: P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0008, P-0010,P-0016, P-0019, P-0025, P-0026, P-0027, P-0028, P-0032, P-0034, P-0035,P-0036, P-0037, P-0038, P-0041, P-0045, P-0050, P-0056, P-0058, P-0059,P-0066, P-0068, P-0079, P-0082, P-0088, P-0090, P-0093, P-0112, P-0114,P-0122, P-0134, P-0155, P-0156, P-0158, P-0163, P-0167, P-0170, P-0184,P-0190, P-0196, P-0204, P-0205, P-0210, P-0228, P-0244, P-0257, P-0262,P-0267, P-0297, P-0302, P-0308, P-0369, P-0442, P-0448, P-0511, P-0519,P-0521, P-0550, P-0559, P-0579, P-0594, P-0599, P-0604, P-0611, P-0624,P-0636, P-0645, P-0668, P-0671, P-0679, P-0685, P-0691, P-0699, P-0700,P-0703, P-0708, P-0716, P-0721, P-0728, P-0734, P-0738, P-0744, P-0745,P-0746, P-0751, P-0753, P-0757, P-0763, P-0773, P-0774, P-0776, P-0798,P-0806, P-0807, P-0841, P-0842, P-0868, P-0884, P-0887, P-0933, P-1042,P-1046

TABLE 2y Compounds with activity toward kinase PDGFRB with IC₅₀ ≦ 10 μMPDGFRB: P-0088, P-0262

TABLE 2z Compounds with activity toward kinase Pim1 with IC₅₀ ≦ 10 μMPim1: P-0024, P-0090

TABLE 2aa Compounds with activity toward kinase PKC theta with IC₅₀ ≦ 10μM PKC P-0001, P-0002, P-0003, P-0004, P-0006, P-0008, P-0011, P-0012,theta: P-0013, P-0014, P-0017, P-0019, P-0020, P-0021, P-0022, P-0024,P-0025, P-0026, P-0030, P-0031, P-0039, P-0044, P-0046, P-0049, P-0051,P-0055, P-0057, P-0060, P-0063, P-0069, P-0070, P-0109, P-0112, P-0238,P-0270

TABLE 2bb Compounds with activity toward kinase Pyk2 with IC₅₀ ≦ 10 μMPyk2: P-0001, P-0010, P-0015, P-0018, P-0021, P-0024, P-0032, P-0041,P-0052, P-0056, P-0058, P-0069, P-0078, P-0086, P-0088, P-0095, P-0112,P-0116, P-0122, P-0137, P-0142, P-0166, P-0178, P-0188, P-0257, P-0262,P-0269, P-0287, P-0318, P-0320, P-0356, P-0369, P-0396, P-0486, P-0501,P-0521, P-0529, P-0550, P-0559, P-0562, P-0611, P-0636, P-0685, P-0697,P-0700, P-0728, P-0753, P-0806, P-0818, P-0837, P-0848, P-0850, P-0851,P-0857, P-0861, P-0866, P-0867, P-0874, P-0883, P-0897, P-0898, P-0910,P-0911, P-0912, P-0919, P-0924, P-0928, P-0944, P-0946, P-0947, P-0957,P-0964, P-0978, P-0991, P-0997, P-1002, P-1010, P-1018, P-1069, P-1280,P-1281, P-1282, P-1288, P-1316, P-1349, P-1365, P-1367, P-1368, P-1370,P-1372, P-1373, P-1375, P-1376, P-1377, P-1379, P-1380, P-1381

TABLE 2cc Compounds with activity toward kinase Ret with IC₅₀ ≦ 10 μMRet: P-0001, P-0001, P-0002, P-0003, P-0003, P-0004, P-0005, P-0005,P-0006, P-0008, P-0009, P-0010, P-0011, P-0012, P-0013, P-0014, P-0015,P-0016, P-0017, P-0019, P-0020, P-0022, P-0024, P-0025, P-0026, P-0027,P-0028, P-0028, P-0029, P-0032, P-0032, P-0033, P-0034, P-0035, P-0036,P-0037, P-0038, P-0039, P-0040, P-0040, P-0041, P-0041, P-0042, P-0043,P-0044, P-0045, P-0046, P-0047, P-0048, P-0049, P-0050, P-0051, P-0052,P-0053, P-0054, P-0055, P-0056, P-0058, P-0059, P-0060, P-0061, P-0062,P-0063, P-0064, P-0065, P-0066, P-0069, P-0070, P-0071, P-0072, P-0073,P-0075, P-0078, P-0079, P-0082, P-0083, P-0085, P-0088, P-0089, P-0090,P-0094, P-0095, P-0096, P-0097, P-0099, P-0100, P-0101, P-0102, P-0103,P-0107, P-0108, P-0109, P-0110, P-0113, P-0114, P-0115, P-0116, P-0117,P-0119, P-0121, P-0122, P-0123, P-0124, P-0134, P-0135, P-0137, P-0138,P-0139, P-0140, P-0141, P-0142, P-0148, P-0152, P-0156, P-0158, P-0159,P-0165, P-0167, P-0171, P-0175, P-0179, P-0181, P-0184, P-0186, P-0190,P-0196, P-0196, P-0204, P-0205, P-0206, P-0210, P-0211, P-0215, P-0218,P-0224, P-0228, P-0231, P-0232, P-0236, P-0244, P-0244, P-0245, P-0246,P-0248, P-0250, P-0257, P-0262, P-0265, P-0269, P-0280, P-0286, P-0289,P-0293, P-0297, P-0302, P-0304, P-0307, P-0308, P-0314, P-0316, P-0316,P-0320, P-0320, P-0321, P-0325, P-0329, P-0339, P-0341, P-0344, P-0347,P-0351, P-0352, P-0363, P-0367, P-0369, P-0371, P-0378, P-0385, P-0392,P-0396, P-0412, P-0418, P-0434, P-0448, P-0448, P-0452, P-0453, P-0453,P-0469, P-0472, P-0486, P-0495, P-0501, P-0501, P-0517, P-0520, P-0521,P-0521, P-0533, P-0536, P-0542, P-0550, P-0550, P-0559, P-0559, P-0561,P-0579, P-0594, P-0596, P-0599, P-0599, P-0604, P-0608, P-0611, P-0623,P-0623, P-0624, P-0624, P-0632, P-0636, P-0638, P-0640, P-0644, P-0645,P-0645, P-0647, P-0656, P-0659, P-0668, P-0668, P-0671, P-0675, P-0678,P-0679, P-0682, P-0683, P-0691, P-0693, P-0697, P-0698, P-0699, P-0700,P-0703, P-0708, P-0710, P-0716, P-0721, P-0726, P-0728, P-0730, P-0734,P-0735, P-0736, P-0737, P-0738, P-0744, P-0745, P-0746, P-0749, P-0751,P-0753, P-0757, P-0761, P-0762, P-0763, P-0771, P-0778, P-0794, P-0795,P-0796, P-0807, P-0810, P-0811, P-0813, P-0822, P-0825, P-0826, P-0835,P-0841, P-0863, P-0865, P-0881, P-0939, P-0976, P-0977, P-0985, P-0998,P-1000, P-1005, P-1007, P-1011, P-1019, P-1024, P-1025, P-1026, P-1029,P-1031, P-1033, P-1036, P-1066, P-1072, P-1073, P-1075, P-1081, P-1085,P-1089, P-1097, P-1111, P-1113, P-1115, P-1117, P-1119, P-1121, P-1125,P-1126, P-1129, P-1130, P-1133, P-1134, P-1135, P-1137, P-1178, P-1181,P-1185, P-1188, P-1189, P-1191, P-1192, P-1193, P-1196, P-1198, P-1200,P-1201

TABLE 2dd Compounds with activity toward kinase Src with IC₅₀ ≦ 10 μMSrc: P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007, P-0008,P-0009, P-0010, P-0016, P-0017, P-0021, P-0025, P-0026, P-0027, P-0028,P-0032, P-0034, P-0035, P-0036, P-0037, P-0038, P-0040, P-0041, P-0045,P-0055, P-0067, P-0068, P-0072, P-0078, P-0079, P-0082, P-0088, P-0090,P-0102, P-0112, P-0114, P-0134, P-0152, P-0166, P-0171, P-0196, P-0209,P-0210, P-0237, P-0244, P-0269, P-0302, P-0316, P-0320, P-0373, P-0396,P-0448, P-0453, P-0483, P-0501, P-0515, P-0521, P-0550, P-0559, P-0562,P-0599, P-0623, P-0624, P-0645, P-0647, P-0668, P-0685, P-0700, P-0721,P-0753, P-0763, P-0771, P-0774, P-0805, P-0806, P-0807, P-0818, P-0837,P-0848, P-0850, P-0851, P-0853, P-0857, P-0866, P-0874, P-0876, P-0877,P-0885, P-0889, P-0898, P-0907, P-0910, P-0933, P-0950, P-0952, P-0955,P-0956, P-0958, P-0997, P-1009, P-1010, P-1013, P-1020, P-1021, P-1181,P-1247, P-1249, P-1250, P-1251, P-1252, P-1253, P-1254, P-1255, P-1256,P-1257, P-1258, P-1261, P-1262, P-1263, P-1264, P-1265, P-1266, P-1267,P-1269, P-1280, P-1281, P-1288, P-1289, P-1316, P-1317, P-1318, P-1336,P-1338, P-1343, P-1345, P-1346, P-1347, P-1348, P-1349, P-1366, P-1383,P-1384, P-1385, P-1387, P-1388, P-1390, P-1391, P-1394, P-1396, P-1397,P-1398, P-1399, P-1403, P-1416, P-1417, P-1431, P-1432, P-1433, P-1445,P-1446, P-1447, P-1448, P-1451, P-1457, P-1459, P-1469, P-1472, P-1473,P-1475, P-1476, P-1477, P-1478, P-1479, P-1480, P-1481, P-1484, P-1485,P-1486, P-1495, P-1496, P-1506, P-1527, P-1530

TABLE 2ee Compounds with activity toward kinase Stk6 with IC₅₀ ≦ 10 μMStk6: P-0001, P-0002, P-0003, P-0007, P-0008, P-0009, P-0010, P-0011,P-0013, P-0014, P-0015, P-0018, P-0020, P-0022, P-0023, P-0029, P-0030,P-0031, P-0032, P-0033, P-0035, P-0040, P-0041, P-0042, P-0043, P-0044,P-0045, P-0046, P-0049, P-0051, P-0052, P-0054, P-0056, P-0057, P-0058,P-0060, P-0061, P-0063, P-0064, P-0065, P-0069, P-0070, P-0071, P-0076,P-0077, P-0080, P-0081, P-0082, P-0086, P-0087, P-0088, P-0091, P-0092,P-0093, P-0094, P-0098, P-0099, P-0100, P-0101, P-0104, P-0105, P-0106,P-0110, P-0111, P-0115, P-0117, P-0118, P-0119, P-0120, P-0123, P-0127,P-0128, P-0129, P-0131, P-0132, P-0133, P-0136, P-0140, P-0143, P-0146,P-0147, P-0148, P-0153, P-0154, P-0155, P-0157, P-0160, P-0162, P-0163,P-0164, P-0169, P-0172, P-0173, P-0174, P-0176, P-0177, P-0179, P-0181,P-0185, P-0187, P-0188, P-0189, P-0191, P-0193, P-0199, P-0201, P-0202,P-0203, P-0206, P-0207, P-0208, P-0212, P-0213, P-0214, P-0221, P-0225,P-0235, P-0237, P-0249, P-0250, P-0251, P-0253, P-0260, P-0261, P-0269,P-0272, P-0276, P-0279, P-0281, P-0283, P-0287, P-0290, P-0295, P-0300,P-0313, P-0317, P-0319, P-0322, P-0345, P-0348, P-0355, P-0370, P-0372,P-0406, P-0407, P-0417, P-0419, P-0426, P-0436, P-0441, P-0445, P-0469,P-0471, P-0489, P-0546, P-0806, P-0885, P-0933, P-0955, P-1013, P-1280,P-1336, P-1394, P-1426

TABLE 2ff Compounds with activity toward kinase Yes with IC₅₀ ≦ 10 μMYes: P-0005, P-0007, P-0010, P-0011, P-0012, P-0013, P-0014, P-0015,P-0016, P-0017, P-0019, P-0020, P-0021, P-0022, P-0024, P-0027, P-0028,P-0029, P-0031, P-0033, P-0036, P-0040, P-0042, P-0043, P-0044, P-0045,P-0046, P-0047, P-0048, P-0049, P-0050, P-0051, P-0052, P-0053, P-0055,P-0056, P-0059, P-0060, P-0061, P-0062, P-0063, P-0065, P-0067, P-0068,P-0070, P-0072, P-0074, P-0075, P-0081, P-0082, P-0083, P-0088, P-0090,P-0093, P-0095, P-0097, P-0101, P-0102, P-0107, P-0109, P-0112, P-0122,P-0124, P-0125, P-0126, P-0129, P-0134, P-0138, P-0139, P-0145, P-0152,P-0153, P-0161, P-0162, P-0166, P-0171, P-0175, P-0188, P-0202, P-0209,P-0210, P-0230, P-0237, P-0271, P-0283, P-0310, P-0327, P-0483, P-0636

TABLE 2gg Compounds with activity toward kinase Zap70 with IC₅₀ ≦ 10 μMZap70: P-0001, P-0004, P-0015, P-0030, P-0032, P-0033, P-0034, P-0035,P-0037, P-0038, P-0040, P-0041, P-0047, P-0058, P-0123, P-0193, P-0195,P-0205, P-0218, P-0228, P-0249, P-0275, P-0296, P-0310, P-0320, P-0342,P-0348, P-0359, P-0360, P-0378, P-0379, P-0387, P-0394, P-0434, P-0442,P-0456, P-0476, P-0484, P-0495, P-0500, P-0507, P-0523, P-0550, P-0586,P-0602, P-0607, P-0611, P-0624, P-0642, P-0649, P-0675, P-0676, P-0694,P-0698, P-0703, P-0716, P-0724, P-0727, P-0755, P-0795, P-0808, P-0836,P-0842, P-0856, P-0859, P-0865, P-0875, P-0878, P-0880, P-0888, P-0929,P-0930, P-0953, P-0982, P-0996, P-1000, P-1005, P-1019, P-1051, P-1073,P-1081, P-1089, P-1119, P-1184, P-1197

TABLE 2hh Compounds with activity toward kinase Akt3 with IC₅₀ ≦ 10 μMAkt3: P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0008, P-0019,P-0021, P-0024, P-0025, P-0026, P-0027, P-0034, P-0035, P-0036, P-0037,P-0038, P-0041, P-0048, P-0055, P-0057, P-0058, P-0060, P-0067, P-0099,P-0112, P-0114, P-0122, P-0127, P-0154, P-0196, P-0270, P-0278, P-0307,P-0329, P-0404, P-0436, P-0573, P-0861, P-0866, P-0883, P-0890, P-0924,P-0936, P-0940, P-0951, P-0952, P-0958, P-0962, P-0978, P-0990, P-0995,P-1010, P-1016, P-1018, P-1021, P-1022, P-1027, P-1034, P-1039, P-1040,P-1043, P-1047, P-1060, P-1062, P-1082, P-1095, P-1139, P-1145, P-1147,P-1150, P-1155, P-1158, P-1172, P-1224, P-1288, P-1459

TABLE 2ii Compounds with activity toward kinase ALK with IC₅₀ ≦ 10 μMALK: P-0806, P-1280, P-1244, P-1336, P-1394, P-1426

TABLE 2jj Compounds with activity toward kinase Cdk2 with IC₅₀ ≦ 10 μMCdk2: P-0806, P-1280, P-1244, P-1394

TABLE 2kk Compounds with activity toward kinase Csk with IC₅₀ ≦ 10 μMCsk: P-0007, P-0805, P-0806, P-0885, P-0933, P-0955, P-0956, P-1013,P-1020, P-1336, P-1394, P-1426

TABLE 2ll Compounds with activity toward kinase EphA2 with IC₅₀ ≦ 10 μMEphA2: P-1336, P-1394

TABLE 2mm Compounds with activity toward kinase EphB4 with IC₅₀ ≦ 10 μMEphB4: P-0806, P-1336

TABLE 2nn Compounds with activity toward kinase Frk with IC₅₀ ≦ 10 μMFrk: P-0007, P-0805, P-0885, P-0933, P-0955, P-0956, P-1013, P-1020,P-1244, P-1318, P-1336, P-1394

TABLE 2oo Compounds with activity toward kinase Gsk3β with IC₅₀ ≦ 10 μMGsk3β: P-0007, P-0015, P-0017, P-0053, P-0057, P-0079, P-0081, P-0085,P-0086, P-0094, P-0104, P-0106, P-0109, P-0123, P-0135, P-0148, P-0154,P-0159, P-0169, P-0180, P-0207, P-0226, P-0236, P-0252, P-0273, P-0462,P-0700, P-0728, P-0763, P-0850, P-0902, P-0913, P-0969, P-1002, P-1142,P-1181, P-1252, P-1317, P-1336, P-1372, P-1426

TABLE 2pp Compounds with activity toward kinase Hck with IC₅₀ ≦ 10 μMHck: P-0007, P-0806, P-0885, P-0933, P-1318, P-1336, P-1394, P-1426

TABLE 2qq Compounds with activity toward kinase MAP4K4 with IC₅₀ ≦ 10 μMMAP4K4: P-0007, P-0057, P-0069, P-0079, P-0082, P-0088, P-0130, P-0131,P-0152, P-0174, P-0176, P-0198, P-0202, P-0214, P-0220, P-0256, P-0269,P-0287, P-0300, P-0317, P-0357, P-0367, P-0369, P-0391, P-0402, P-0442,P-0449, P-0477, P-0488, P-0495, P-0518, P-0527, P-0537, P-0573, P-0601,P-0685, P-0695, P-0700, P-0728, P-0734, P-0753, P-0800, P-0806, P-0811,P-0850, P-0851, P-0853, P-0862, P-0885, P-0896, P-0902, P-0904, P-0909,P-0913, P-0931, P-0933, P-0937, P-0954, P-0958, P-0971, P-0986, P-1017,P-1042, P-1056, P-1252, P-1253, P-1279, P-1280, P-1289, P-1317, P-1318,P-1336, P-1372, P-1383, P-1394, P-1406, P-1411, P-1414, P-1415, P-1417,P-1418, P-1426, P-1429, P-1685

TABLE 2rr Compounds with activity toward kinase IGF1R with IC₅₀ ≦ 10 μMIGF1R: P-0002, P-0003, P-0004, P-0009, P-0031, P-0079, P-0080, P-0084,P-0115, P-0136, P-0154, P-0157, P-0212, P-0213, P-0700, P-0716, P-0746,P-0850, P-1336, P-1337, P-1390, P-1394

TABLE 2ss Compounds with activity toward kinase IKK beta with IC₅₀ ≦ 10μM IKK beta: P-0007, P-0013, P-0014, P-0029, P-0057, P-0073, P-0084,P-0085, P-0086, P-0087, P-0096, P-0098, P-0106, P-0111, P-0115, P-0120,P-0127, P-0128, P-0133, P-0135, P-0163, P-0164, P-0172, P-0177, P-0179,P-0216, P-0270, P-0272, P-0315, P-0376, P-0404, P-0410, P-0436, P-0629,P-0682, P-0690, P-0790, P-0896, P-0920, P-0962, P-1223

TABLE 2tt Compounds with activity toward kinase Itk with IC₅₀ ≦ 10 μMItk: P-0002, P-0003, P-0004, P-0006, P-0008, P-0009, P-0013, P-0016,P-0019, P-0020, P-0024, P-0025, P-0027, P-0031, P-0034, P-0035, P-0036,P-0038, P-0067, P-0173, P-0196, P-0521, P-0579, P-0716, P-0778, P-0883,P-0951, P-1016, P-1067, P-1337, P-1385

TABLE 2uu Compounds with activity toward kinase Jak3 with IC₅₀ ≦ 10 μMJak3: P-0003, P-0004, P-0009, P-0013, P-0014, P-0019, P-0020, P-0022,P-0024, P-0034, P-0039, P-0044, P-0046, P-0049, P-0051, P-0060, P-0061,P-0063, P-0070, P-0084, P-0101, P-0106, P-0108, P-0109, P-0119, P-0122,P-0124, P-0138, P-0141, P-0146, P-0171, P-0178, P-0187, P-0215, P-0318,P-0521, P-0730, P-0863, P-01367, P-01385

TABLE 2vv Compounds with activity toward kinase MLK1 with IC₅₀ ≦ 10 μMMLK1: P-1336, P-1426

TABLE 2ww Compounds with activity toward kinase TrkA with IC₅₀ ≦ 10 μMTrkA: P-0409, P-0806, P-1244, P-1426

TABLE 2xx Compounds with activity toward kinase PDGFRA with IC₅₀ ≦ 10 μMPDGFRA: P-0007, P-0409, P-0806, P-0885, P-0933, P-1280, P-1336, P-1394,P-1426

TABLE 2yy Compounds with activity toward kinase Plk1 with IC₅₀ ≦ 10 μMPlk1: P-0018, P-0022, P-0031, P-0044, P-0046, P-0067, P-0075, P-0083,P-0085, P-0099, P-0113, P-0123, P-0128, P-0135, P-0146, P-0148, P-0154,P-0178, P-0286, P-0332, P-0345, P-0366, P-0480, P-0490, P-0581, P-0863,P-0954, P-1138

TABLE 2zz Compounds with activity toward kinase Brk with IC₅₀ ≦ 10 μMBrk: P-0007, P-0805, P-0806, P-0885, P-0933, P-0955, P-0956, P-1013,P-1020, P-1244, P-1318, P-1336, P-1394

TABLE 2ab Compounds with activity toward kinase ROCK1 with IC₅₀ ≦ 10 μMROCK1: P-0057

TABLE 2ac Compounds with activity toward kinase Syk with IC₅₀ ≦ 10 μMSyk: P-0002, P-0010, P-0033, P-0054, P-0056, P-0057, P-0089, P-0196,P-0448, P-0521, P-0599, P-1336

TABLE 2ad Compounds with activity toward kinase TEC with IC₅₀ ≦ 10 μMTEC: P-0017, P-0033, P-0044, P-0088, P-0156, P-0166, P-0228, P-0257,P-0297, P-0429, P-0897, P-0954, P-0983, P-0991, P-0997, P-1020, P-1317

TABLE 2ae Compounds with activity toward kinase Tie2 with IC₅₀ ≦ 10 μMTie2: P-0806, P-1280, P-1336, P-1394, P-1426

Plasmid sequence and PCR primer information:

Abl PCR primers Abl ABL-227 CACCACGGTGTGTCCCCCAACTACGA 1424(SEQ ID NO:_) CABL-A TGTCACGTCGACTCAGACGCCTTGTTTCCCCAGCT  736(SEQ ID NO:_) P1121. pET-SPEC BI-PTP Abl G227-V515-Xtaatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggtcaccaccatcaccaccacggtgtgtcc                            M  G  H  H  H  H  H  H  G  V  Scccaactacgacaagtgggagatggaacgcacggacatcaccatgaagcacaagctgggc P  N  Y  D  K  W  E  M  E  R  T  D  I  T  M  K  H  K  L  Ggggggccagtacggggaggtgtacgagggcgtgtggaagaaatacagcctgacggtggcc G  G  Q  Y  G  E  V  Y  E  G  V  W  K  K  Y  S  L  T  V  Agtgaagaccttgaaggaggacaccatggaggtggaagagttcttgaaagaagctgcagtc V  K  T  L  K  E  D  T  M  E  V  E  E  F  L  K  E  A  A  Vatgaaagagatcaaacaccctaacctggtgcagctccttggggtctgcacccgggagccc M  K  E  I  K  H  P  N  L  V  Q  L  L  G  V  C  T  R  E  Pccgttctatatcatcactgagttcatgacctacgggaacctcctggactacctgagggag P  F  Y  I  I  T  E  F  M  T  Y  G  N  L  L  D  Y  L  R  Etgcaaccggcaggaggtgaacgccgtggtgctgctgtacatggccactcagatctcgtca C  N  R  Q  E  V  N  A  V  V  L  L  Y  M  A  T  Q  I  S  Sgccatggagtacctggagaagaaaaacttcatccacagagatcttgctgcccgaaactgc A  M  E  Y  L  E  K  K  N  F  I  H  R  D  L  A  A  R  N  Cctggtaggggagaaccacttggtgaaggtagctgattttggcctgagcaggttgatgaca L  V  G  E  N  H  L  V  K  V  A  D  F  G  L  S  R  L  M  Tggggacacctacacagcccatgctggagccaagttccccatcaaatggactgcacccgag G  D  T  Y  T  A  H  A  G  A  K  F  P  I  K  W  T  A  P  Eagcctggcctacaacaagttctccatcaagtccgacgtctgggcatttggagtattgctt S  L  A  Y  N  K  F  S  I  K  S  D  V  W  A  F  G  V  L  Ltgggaaattgctacctatggcatgtccccttacccgggaattgacctgtcccaggtgtat W  E  I  A  T  Y  G  M  S  P  Y  P  G  I  D  L  S  Q  V  Ygagctgctagagaaggactaccgcatggagcgcccagaaggctgcccagagaaggtctat E  L  L  E  K  D  Y  R  M  E  R  P  E  G  C  P  E  K  V  Ygaactcatgcgagcatgttggcagtggaatccctctgaccggcoctcctttgctgaaatc E  L  M  R  A  C  W  Q  W  N  P  S  D  R  P  S  F  A  E  Icaccaagcctttgaaacaatgttccaggaatccagtatctcagacgaagtggaaaaggag H  Q  A  F  E  T  M  F  Q  E  S  S  I  S  D  E  V  E  K  Ectggggaaacaaggcgtctgagtcgac (SEQ ID NO:_) L  G  K  Q  G  V  -        (SEQ ID NO:_)

B-Raf V600E PCR primers BRAF BRAF437D-SACGGGACCATATGGATGATTGGGAGATTCCTGA 4783 (SEQ ID NO:_) BRAF722K-ACACTGGTCGACTATTTTGGCAATGAGCGGGCCA 4784 (SEQ ID NO:_) BRAFV599E-SGGTCTACCTACAGAAAAATCTCGATGGAG  893 (SEQ ID NO:_) BRAFV599E-ACTCCATCGAGATTTTTCTGTAGCTAGACC  894 (SEQ ID NO:_)P4254. pFastBacBD-CDC37 BRAF D437-K722-X, V600E     tattccggattattcataccgtcccaccatcgggcgcggatctcggtccgaaaccatgtcgtactaccatcaccatcaccatcacgattacgatatcccaacgaccgaaaacctg M  S  Y  Y  H  H  H  H  H  H  D  Y  D  I  P  T  T  E  N  Ltattttcagggccatatggatgattgggagattcctgatgggcagattacagtgggacaa Y  F  Q  G  H  M  D  D  W  E  I  P  D  G  Q  I  T  V  G  Qagaattggatctggatcatttggaacagtctacaagggaaagtggcatggtgatgtggca R  I  G  S  G  S  F  G  T  V  Y  K  G  K  W  H  G  D  V  Agtgaaaatgttgaatgtgacagcacctacacctcagcagttacaagccttcaaaaatgaa V  K  M  L  N  V  T  A  P  T  P  Q  Q  L  Q  A  F  K  N  Egtaggagtactcaggaaaacacgacatgtgaatatcctactcttcatgggctattccaca V  G  V  L  R  K  T  R  H  V  N  I  L  L  F  M  G  Y  S  Taagccacaactggctattgttacccagtggtgtgagggctccagcttgtatcaccatctc K  P  Q  L  A  I  V  T  Q  W  C  E  G  S  S  L  Y  H  H  Lcatatcattgagaccaaatttgagatgatcaaacttatagatattgcacgacagactgca H  I  I  E  T  K  F  E  M  I  K  L  I  D  I  A  R  Q  T  Acagggcatggattacttacacgccaagtcaatcatccacagagacctcaagagtaataat Q  G  M  D  Y  L  H  A  K  S  I  I  H  R  D  L  K  S  N  Natatttcttcatgaagacctcacagtaaaaataggtgattttggtctagctacagaaaaa I  F  L  H  E  D  L  T  V  K  I  G  D  F  L  A  T  E  E  Ktctcgatggagtgggtcccatcagtttgaacagttgtctggatccattttgtggatggca S  R  W  S  G  S  H  Q  F  E  Q  L  S  G  S  I  L  W  M  Accagaagtcatcagaatgcaagataaaaatccatacagctttcagtcagatgtatatgca P  E  V  I  R  M  Q  D  K  N  P  Y  S  F  Q  S  D  V  Y  Atttggaattgttctgtatgaattgatgactggacagttaccttattcaaacatcaacaac F  G  I  V  L  Y  E  L  M  T  G  Q  L  P  Y  S  N  I  N  Nagggaccagataatttttatggtgggacgaggatacctgtctccagatctcagtaaggta R  D  Q  I  I  F  M  V  G  R  G  Y  L  S  P  D  L  S  K  Vcggagtaactgtccaaaagccatgaagagattaatggcagagtgcctcaaaaagaaaaga R  S  N  C  P  K  A  M  K  R  L  M  A  R  C  L  K  K  K  Rgatgagagaccactctttccccaaattctcgcctctattgagctgctggcccgctcattg D  E  R  P  L  F  P  Q  I  L  A  S  E  L  L  A  A  R  S  Lccaaaatagtcgactagagcctgcagtctcgaggcatgcggtaccaagctt (SEQ ID NO:_) P  K  -                                            (SEQ ID NO:_)

Erk2 PCR primers ERK2 ERK2-S GGCAGCCCATATGGCGGCGGCGGCGGCGGC 748(SEQ ID NO:_) ERK2-A TGTCCGTCGACATTTAAGATCTGTATCCTGG 749 (SEQ ID NO:_)P4227.pET15S ERK2/MEK1DDtaatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggcagcagccatcatcatcatcatcacagc                            M  G  S  S  H  H  H  H  H  H  Sagcggcctggtgccgcgcggcagccatatggcggcggcggcgggcgcgggcccggagatg S  G  L  V  P  R  G  S  H  M  A  A  A  A  G  A  G  P  E  Mgtccgcgggcaggtgttcgacgtggggccgcgctacaccaacctctcgtacatcggcgag V  R  G  Q  V  F  D  V  G  P  R  Y  T  N  L  S  Y  I  G  Eggcgcctacggcatggtgtgctctgcttatgataatgtcaacaaagttcgagtagctatc G  A  Y  G  M  V  C  S  A  Y  D  N  V  N  K  V  R  V  A  Iaagaaaatcagcccctttgagcaccagacctactgccagagaaccctgagggagataaaa K  K  I  S  P  F  E  H  Q  T  Y  C  Q  R  T  L  R  E  I  Katcttactgcgcttcagacatgagaacatcattggaatcaatgacattattcgagcacca I  L  L  R  F  R  H  E  N  I  I  G  I  N  D  I  I  R  A  Paccatcgagcaaatgaaagatgtatatatagtacaggacctcatggaaacagatctttac T  I  E  Q  M  K  D  V  Y  I  V  Q  D  L  M  E  T  D  L  Yaagctcttgaagacacaacacctcagcaatgaccatatctgctattttctctaccagatc K  L  L  K  T  Q  H  L  S  N  D  H  I  C  Y  F  L  Y  Q  Ictcagagggttaaaatatatccattcagctaacgttctgcaccgtgacctcaagccttcc L  R  G  L  K  Y  I  H  S  A  N  V  L  H  R  D  L  K  P  Saacctgctgctcaacaccacctgtgatctcaagatctgtgactttggcctggcccgtgtt N  L  L  L  N  T  T  C  D  L  K  I  C  D  F  G  L  A  R  Vgcagatccagaccatgatcacacagggttcctgacagaatatgtggccacacgttggtac A  D  P  D  H  D  H  T  G  F  L  T  E  Y  V  A  T  R  W  Yagggctccagaaattatgttgaattccaagggctacaccaagtccattgatatttggtct R  A  P  E  I  M  L  N  S  K  G  Y  T  K  S  I  D  I  W  Sgtaggctgcattctggcagaaatgctttctaacaggcccatctttccagggaagcattat V  G  C  I  L  A  E  M  L  S  N  R  P  I  F  P  G  K  H  Ycttgaccagctgaaccacattttgggtattcttggatccccatcacaagaagacctgaat L  D  Q  L  N  H  I  L  G  I  L  G  S  P  S  Q  E  D  L  Ntgtataataaatttaaaagctaggaactatttgctttctcttccacacaaaaataaggtg C  I  I  N  L  K  A  R  N  Y  L  L  S  L  P  H  K  N  K  Vccatggaacaggctgttcccaaatgctgactccaaagctctggacttattggacaaaatg P  W  N  R  L  F  P  N  A  D  S  K  A  L  D  L  L  D  K  Mttgacattcaacccacacaagaggattgaagtagaacaggctctggcccacccatatctg L  T  F  N  P  H  K  R  I  E  V  E  Q  A  L  A  H  P  Y  Lgagcagtattacgacccgagtgacgagcccatcgccgaagcaccattcaagttcgacatg E  Q  Y  Y  D  P  S  D  E  P  I  A  E  A  P  F  K  F  D  Mgaattggatgacttgcctaaggaaaagctcaaagaactaatttttgaagagactgctaga E  L  D  D  L  P  K  E  K  L  K  E  L  I  F  F  E  T  A  Rttccagccaggatacagatcttaaatgtcgac (SEQ ID NO:_) F  Q  P  G  Y  R  S  -          (SEQ TO NO:_)

Fak PCR primers FAK FAK411 GCTGGATCCACCAGGGATTATGAGATTCAAAG 2156(SEQ ID NO:_) FAK686 GTTCTTGTCGACTACTGAGCCTTCTCTTCCTCCA 2157(SEQ ID NO:_) P1358.pFastBacHtb FAK 5411-Q686-X     tattccggattattcataccgtcccaccatcgggcgcggatctcggtccgaaaccatgtcgtactaccatcaccatcaccatcacgattacgatatcccaacgaccgaaaacctg M  S  Y  Y  H  H  H  H  H  H  D  Y  D  I  P  T  T  E  N  Ltattttcagggcgccatgggatccaccagggattatgagattcaaagagaaagaatagaa Y  F  Q  G  A  M  G  S  T  R  D  Y  E  I  Q  R  E  R  I  Ecttggacgatgtattggagaaggccaatttggagatgtacatcaaggcatttatatgagt L  G  R  C  I  G  E  G  Q  F  G  D  V  H  Q  G  I  Y  M  Sccagagaatccagctttggcggttgcaattaaaacatgtaaaaactgtacttcggacagc P  E  N  P  A  L  A  V  A  I  K  T  C  K  N  C  T  S  D  Sgtgagagagaaatttcttcaagaagccttaacaatgcgtcagtttgaccatcctcatatt V  R  E  K  F  L  Q  E  A  L  T  M  R  Q  F  D  H  P  H  Igtgaagctgattggagtcatcacagagaatcctgtctggataatcatggagctgtgcaca V  K  L  I  G  V  I  T  E  N  P  V  W  I  I  M  E  L  C  Tcttggagagctgaggtcatttttgcaagtaaggaaatacagtttggatctagcatctttg L  G  E  L  R  S  F  L  Q  V  R  K  Y  S  L  D  L  A  S  Latcctgtatgcctatcagcttagtacagctcttgcatatctagagagcaaaagatttgta I  L  Y  A  Y  Q  L  S  T  A  L  A  Y  L  E  S  K  R  F  Vcacagggacattgctgctcggaatgttctggtgtcctcaaatgattgtgtaaaattagga H  R  D  I  A  A  R  N  V  L  V  S  S  N  D  C  V  K  L  Ggactttggattatcccgatatatggaagatagtacttactacaaagcttccaaaggaaaa D  F  G  L  S  R  Y  M  E  D  S  T  Y  Y  K  A  S  K  G  Kttgcctattaaatggatggctccagagtcaatcaattttcgacgttttacctcagctagt L  P  I  K  W  M  A  P  E  S  I  N  F  R  R  F  T  S  A  Sgacgtatggatgtttggtgtgtgtatgtgggagatactgatgcatggtgtgaagcctttt D  V  W  M  F  G  V  C  M  W  E  I  L  M  H  G  V  K  P  Fcaaggagtgaagaacaatgatgtaatcggtcgaattgaaaatggggaaagattaccaatg Q  G  V  K  N  N  D  V  I  G  R  I  E  N  G  E  R  L  P  Mcctccaaattgtcctcctaccctatacagccttatgacgaaatgctgggcctatgacccc P  P  N  C  P  P  T  L  Y  S  L  M  T  K  C  W  A  Y  D  Pagcaggcggcccaggtttactgaacttaaagctcagctcagcacaatcctggaggaagag S  R  R  P  R  F  T  E  L  K  A  Q  L  S  T  I  L  E  E  Eaaggctcagtagtcgacgagctcactagtcgcggccgctttcgaatctagagcctgcagt K  A  Q  -  S  T  S  S  L  V  A  A  A  F  E  S  R  A  C  Sctcgaggcatgcggtaccaagcttgtcgagaagtactagaggatcataatc (SEQ ID NO:_) L  E  A  C  G  T  K  L  V  E  K  Y  -              (SEQ ID NO:_)

FGFR1 PCR primers FGFR1 FGFR1-S GACTCCTCATATGGCAGCCGTCTGAGTATGA 1237(SEQ ID NO:_) FGFR-SAL CAGGTCGTCGACTACTCCTGGTTGGAGGTCAAGG 1611(SEQ ID NO:_) C488A-1 CTGGGAGAGGGCGCGTTTGGGCAGGTGG 2038 (SEQ ID NO:_)C488A-2 CCACCTGCCCAAACGCGCCCTCTCCCAG 2039 (SEQ ID NO:_) C584S-1CAGGGCTGGAATACAGCTACAACCCCAGC 2041 (SEQ ID NO:_) C584S-2GCTGCGGTTGTAGCTGTATTCCAGCCCTG 2042 (SEQ ID NO:_)P1351.pET N6 BI-PTP FGFR A458-E765-X C488A, C584Staatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggtcaccaccatcaccatcatatggcaggg                            M  G  H  H  H  H  H  H  M  A  Ggtctctgagtatgagcttcccgaagaccctcgctgggagctgcctcgggacagactggtc V  S  E  Y  E  L  P  E  D  P  R  W  E  L  P  R  D  R  L  Vttaggcaaacccctgggagagggcgcgtttgggcaggtggtgttggcagaggctatcggg L  G  K  P  L  G  E  G  A  F  G  Q  V  V  L  A  E  A  I  Gctggacaaggacaaacccaaccgtgtgaccaaagtggctgtgaagatgttgaagtcggac L  D  K  D  K  P  N  R  V  T  K  V  A  V  K  M  L  K  S  Dgcaacagagaaagacttgtcagacctgatctcagaaatggagatgatgaagatgatcggg A  T  E  K  D  L  S  D  L  I  S  E  M  E  M  M  K  M  I  Gaagcataagaatatcatcaacctgctgggggcctgcacgcaggatggtcccttgtatgtc K  H  K  N  I  I  N  L  L  G  A  C  T  Q  D  G  P  L  Y  Vatcgtggagtatgcctccaagggcaacctgcgggagtacctgcaggcccggaggccccca I  V  E  Y  A  S  K  G  N  L  R  E  Y  L  Q  A  R  R  P  Pgggctggaatacagctacaaccccagccacaacccagaggagcagctctcctccaaggac G  L  E  Y  S  Y  N  P  S  H  N  P  E  E  Q  L  S  S  K  Dctggtgtcctgcgcctaccaggtggcccgaggcatggagtatctggcctccaagaagtgc L  V  S  C  A  Y  Q  V  A  R  G  M  E  Y  L  A  S  K  K  Catacaccgagacctggcagccaggaatgtcctggtgacagaggacaatgtgatgaagata I  H  R  D  L  A  A  R  N  V  L  V  T  E  D  N  V  M  K  Igcagactttggcctcgcacgggacattcaccacatcgactactataaaaagacaaccaac A  D  F  G  L  A  R  D  I  H  H  I  D  Y  Y  K  K  T  T  Nggccgactgcctgtgaagtggatggcacccgaggcattatttgaccggatctacacccac G  R  L  P  V  K  W  M  A  P  E  A  L  F  D  R  I  Y  T  Hcagagtgatgtgtggtctttcggggtgctcctgtgggagatcttcactctgggcggctcc Q  S  D  V  W  S  E  G  V  L  L  W  E  I  F  T  L  G  G  Sccataccccggtgtgcctgtggaggaacttttcaagctgctgaaggagggtcaccgcatg P  Y  P  G  V  P  V  E  E  L  F  K  L  L  K  E  G  H  R  Mgacaagcccagtaactgcaccaacgagctgtacatgatgatgcgggactgctggcatgca D  K  P  S  N  C  T  N  E  L  Y  M  M  M  R  D  C  W  H  Agtgccctcacagagacccaccttcaagcagctggtggaagacctggaccgcatcgtggcc V  P  S  Q  R  P  T  F  K  Q  L  V  E  D  L  D  R  I  V  Attgacctccaaccaggagtagtcgacgaaggagatatatcc (SEQ ID NO:_) L  T  S  N  Q  E  -  -                   (SEQ ID NO:_)

Flt1 PCR primers FLT1 FLT1-S ATCAATTCATATGGACCCAGATGAAGTTCC 737(SEQ ID NO:_) FLT1-A ATGTAGTCGACCTAATCCTGTTGTACATTTGCTT 738(SEQ ID NO:_) P1826.pETN6 BI-PTP FLT1 M799-D1165-X WTtaatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggtcaccaccatcaccatcatatggaccca                            M  G  H  H  H  H  H  H  M  D  Pgatgaagttcctttggatgagcagtgtgagcggctcccttatgatgccagcaagtgggag D  E  V  P  L  D  E  Q  C  E  R  L  P  Y  D  A  S  K  W  Etttgcccgggagagacttaaactgggcaaatcacttggaagaggggcttttggaaaagtg F  A  R  E  R  L  K  L  G  K  S  L  G  R  G  A  F  G  K  Vgttcaagcatcagcatttggcattaagaaatcacctacgtgccggactgtggctgtgaaa V  Q  A  S  A  F  G  I  K  K  S  P  T  C  R  T  V  A  V  Katgctgaaagagggggccacggccagcgagtacaaagctctgatgactgagctaaaaatc M  L  K  E  G  A  T  A  S  E  Y  K  A  L  M  T  E  L  K  Ittgacccacattggccaccatctgaacgtggttaacctgctgggagcctgcaccaagcaa L  T  H  I  G  H  H  L  N  V  V  N  L  L  G  A  C  T  K  Qggagggcctctgatggtgattgttgaatactgcaaatatggaaatctctccaactacctc G  G  P  L  M  V  I  V  E  Y  C  K  Y  G  N  L  S  N  Y  Laagagcaaacgtgacttattttttctcaacaaggatgcagcactacacatggagcctaag K  S  K  R  D  L  E  F  L  N  K  D  A  A  L  H  M  E  P  Kaaagaaaaaatggagccaggcctggaacaaggcaagaaaccaagactagatagcgtcacc K  E  K  M  E  P  G  L  E  O  G  K  K  P  R  L  D  S  V  Tagcagcgaaagctttgcgagctccggctttcaggaagataaaagtctgagtgatgttgag S  S  E  S  F  A  S  S  G  F  Q  E  D  K  S  L  S  D  V  Egaagaggaggattctgacggtttctacaaggagcccatcactatggaagatctgatttct E  E  E  D  S  D  G  F  Y  K  E  P  I  T  M  E  D  L  I  Stacagttttcaagtggccagaggcatggagttcctgtcttccagaaagtgcattcatcgg Y  S  F  Q  V  A  R  G  M  E  F  L  S  S  R  K  C  I  H  Rgacctggcagcgagaaacattcttttatctgagaacaacgtggtgaagatttgtgatttt D  L  A  A  R  N  I  L  L  S  E  N  N  V  V  K  I  C  D  Fggccttgcccgggatatttataagaaccccgattatgtgagaaaaggagatactcgactt G  L  A  R  D  I  Y  K  N  P  D  Y  V  R  K  G  D  T  R  Lcctctgaaatggatggctcccgaatctatctttgacaaaatctacagcaccaagagcgac P  L  K  W  M  A  P  E  S  I  F  D  K  I  Y  S  T  K  S  Dgtgtggtcttacggagtattgctgtgggaaatcttctccttaggtgggtctccataccca V  W  S  Y  G  V  L  L  W  E  I  F  S  L  G  G  S  P  Y  Pggagtacaaatggatgaggacttttgcagtcgcctgagggaaggcatgaggatgagagct G  V  Q  M  D  E  D  F  C  S  R  L  R  E  G  M  R  M  R  Acctgagtactctactcctgaaatctatcagatcatgctggactgctggcacagagaccca P  E  Y  S  T  P  E  I  Y  Q  T  M  L  D  C  W  H  R  D  Paaagaaaggccaagatttgcagaacttgtggaaaaactaggtgatttgcttcaagcaaat K  E  R  P  R  F  A  E  L  V  E  R  L  G  D  L  L  Q  A  Ngtacaacaggattaggtcgaccaccaccaccaccaccactgagatccggctggccctact V  Q  Q  D  -  (SEQ ID NO:_)ggccgaaaggaattcgaggccagcagggccaccgctgagcaataactagcataaccccttggggcctctaaacgggtcttgaggggttttttg (SEQ ID NO: )

Kit PCR primers KIT 8K1A ATOTACCAAGTTCAGTCGAAAGTTGTTGAAGAAATCAACGG 1775(SEQ ID NO:_) 8K1B GCTCGATGTAAACCTAGTTGTTACCGTTGATTTCTTCAACAACTTT 1777(SEQ ID NO:_) 8K2A AACAACTACGTTTACATCGACCCGACCCAGCTGCCSTACGAC 1779(SEQ ID NO:_) 8K2B GTTACGGGGCAACTCCCATTTGTGGTCGTACGGCAGCTGGGTC 1781(SEQ ID NO:_) 8K3A AAATGGGAGTTCCCGCGTAACCGTCTGTCTTTCGGTAAAACCC 1782(SEQ ID NO:_) 8K3B ACCGAACGCACCCGCACCCAGGGTTTTACCGAAAGACAGAC 1783(SEQ ID NO:_) 8K4A GGTGCGGGTGCGTTCGGTAAAGTTGTTGAAGGGACCGCCTACG 1784(SEQ ID NO:_) 8K4B GCCGCGTCAGATTTGATCAGACCGTACGCGGTCGCTTCAAC 1785(SEQ ID NO:_) 8K5A CTGATCAAATCTGACGCGGCGATGACCGTTGCCGTTAAAATGC 1736(SEQ ID NO:_) 8K5B GTCAGGTGCGCAGACCGTTTCAGCATTTTAACCGCAACGGTCA 1787(SEQ ID NO:_) 8K6A AAACCGTCTGCGCACCTGACCGAACGTGAAGCGCTGATCTCTG 1788(SEQ ID NO:_) 8K6B CCAGGTAAGACAGAACTTTCAGTTCAGACATCAGCGCTTCACGT 1789(SEQ ID NO:_) 8K7A CTGAAAGTTCTGTCTTACCTGGGTAACCACATGAACATCGTTAA 1791(SEQ ID NO:_) 8K7B GGTGCACGCACCCACCAGGTTAACGATCTTCATGTGGTTAC 1792(SEQ ID NO:_) 8K8A CTGCTGGGTGCGTGCACCATCGGTGGTCCGACCCTGGTTATCA 1793(SEQ ID NO:_) 8K8B GTCACCGTAGCASCACTATTCGGTGATAACCAGGGTCGGACCA 1794(SEQ ID NO:_) 8K9A GAATACTGCTGCTACGGTGACCTGCTGAACTTCCTGCGTCGTA 1795(SEQ ID NO:_) 8K9B AGAGCAGATGAAAGAGTCACGTTTACGACGCAGGAAGTTCAGC 1796(SEQ ID NO:_) 8K10A CGTGACTCTTTCATCTGCTCTAAACAGGAAGACCACGCGGAAG 1797(SEQ ID NO:_) 8K10B CAGCAGGTTTTTGTACAGCCCCGCTTCCGCGTGGTCTTCCTGT 1798(SEQ ID NO:_) 8K11A GCGCTGTACAAAAACCTGCTGCACTCTAAAGAATCTTCTTGCTC 1799(SEQ ID NC:_) 8K11B CCATGTATTCCTTGGTAGAGTCACAGCAACAAGATTCTTTACAGT 1811(SEQ ID NO:_) 8K11A GACTCTACCAACCAATACATGGACATGAAACCGGGTGTTTCTTA 1812(SEQ ID NO:_) 8K11B TCCGCTTTGGTCGGAACAACGTAAGAAACACCCGGTTTCATGT 1813(SEQ ID NO:_) 8K12A GTTGTTCCGACCAAAGCGGACAAACGTCGTTCTGTTCGTATCG 1814(SEQ ID NO:_) 8K12B TAACGTCACGTTCGATGTAAGAACCGATACGAACAGAACGACGTTT 1815(SEQ ID NO:_) 8K13A TCTTACATCGAACGTGACGTTACCCCGGCGATCATGGAAGACG 1816(SEQ ID NO:_) 8K13B CCAGGTCCAGCGCCAGTTCGTCGTCTTCCATGATCGCCGG 1817(SEQ ID NO:_) 8K14A GAACTGGCGCTGGACCTGGAAGACCTGCTGTCTTTCTCTTACC 1818(SEQ ID NO:_) 8K14B GAACGCCATACCTTTCGCCCTGGTAAGAGAAAGACAGCAGGT 1819(SEQ ID NO:_) 8K15A GTTGCGAAGGTATGGCGTTCCTGGCGTCTAAAACTGCATCCA 1821(SEQ ID NO:_) 8K15B CGCGCCGCCAGGTCACGGTGGATGCAGTTTTTACACGCC 1822(SEQ ID NO:_) 8K16A CGTGACCTGGCGGCGCGTAACATCCTGCTGACCCACGGTCG 1823(SEQ ID NO:_) 8K16B ACCGAAGTCGCAGATTTTGGTGATACGACCGTGGGTCAGCAGG 1824(SEQ ID NO:_) 8K17A ACCAAAATCTGCGACTTCGGTCTGGCGCGTGACATCAAAAACG 1825(SEQ ID NO:_) 8K17B GTTACCTTTAACAACGTAGTTAGAGTCGTTTTTGATGTCACGCGCC 1826(SEQ ID NO:_) 8K18A TCTAACTACGTTGTTAAAGGTAACGCGCGTCTGCCGCTTAAATG 1827(SEQ ID NO:_) 8K18B GAAGATACATTCCGGCGCCATCCATTTAACCGGCACACCCGC 1829(SEQ ID NO:_) 8K19A ATGGCGCCGGAATCTATCTTCAACTGCGTTTACACCTTCGAATC 1831(SEQ ID NO:_) 8K19B GATACCGTAAGACCAAACGTCAGATTCGAAGGTGTAAACGCAG 1832(SEQ ID NO:_) 8K20A GACGTTTGGTCTTACGGTATCTTCCTGTGGGAACTGTTCTCTC 1833(SEQ ID NO:_) 8K20B CCTGTGGGAACTGTTCTCTCTGGGTTCTTCTCCCTACCCGG 1834(SEQ ID NO:_) 8K21A GGTTCTTCTCCGTACCCGGGTATGCCGGTTGACTCTAAATTCTAT 1835(SEQ ID NO:_) 8K21B CGGAAACCTTCTTTGATCATTTTGTAGAATTTAGAGTCAACCGGC 1836(SEQ ID NO:_) 8K22A AAAATGATCAAAGAAGGTTTCCGTATGCTGTCTCCGGAACACG 1837(SEQ ID NO:_) 8K22B ATGTCGTACATTTCCGCCCGCCCGTGTTCCGGAGACAGATA 1838(SEQ ID NO:_) 8K23A CCGGCGGAAATGTACGACATCATCAAAACCTGCTGGGACGCG 1839(SEQ ID NO:_) 8K23B AAGGTCGGACGTTTCAGCGGGTCCGCGTCCCAGCAGGTTTTC 1841(SEQ ID NO:_) 8K24A CCGCTGAAACGTCCGACCTTCAAACAGATCGTTCAGCTGATCG 1842(SEQ ID NO:_) 8K24B TTGGTAGATTCAGAGATCTGTTTTTCGATCAGCTGAACGATCTGTT 1843(SEQ ID NO:_) 8K25A AAACAGATCTCTGAATCTACCAACCACATCTACTCTAACCTGGC 1844(SEQ ID NO:_) 8K25B TGACGGTTCGGAGAGCAGTTCGCCAGGTTAGAGTAGATGTGG 1845(SEQ ID NO:_) 8K26A AACTGCTCTCCGAACCGTCAGAAACCCCTTGTTGACCACTCTC 1846(SEQ ID NO:_) 8K26B GTAGAACCAACAGAGTTGATACGAACAGAGTGGTCAACAACCGCT 1847(SEQ ID NO:_) 8K27A CGTATCAACTCTCTTCGTTCTACCCCGTCTTCTTCTCACCCG 1848(SEQ ID NO:_) 8K27B AACGTCGTCGTGAACCAGCAGCGGCTGAGAAGAACACGCC 1849(SEQ ID NO:_) 8K-F GTTGTTTCATATCTACCAAGTTCAGTCCAAAG 1851 (SEQ ID NO:_)8K-R GTTGTTTGTCGACTAAACGTCGTCGTCCCAG 1852 (SEQ ID NO:_) KIT COD-K948XGTTCTTGTCGACTATTTCTGACGGTTCGGAGAGC 3411 (SEQ ID NO:_)P1332.N6 BI PTP KIT M552-K948-X CODtaatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggtcaccaccatcaccatcatatgtacgaa                            M  G  H  H  H  H  H  H  M  Y  Egttcagtggaaagttgttgaagaaatcaacggtaacaactacgtttacatcgacccgacc V  Q  W  K  V  V  E  E  I  N  G  N  N  Y  V  Y  I  D  P  Tcagctgccgtacgaccacaaatgggagttcccgcgtaaccgtctgtctttcggtaaaacc Q  L  P  Y  D  H  K  W  E  F  P  R  N  R  L  S  F  G  K  Tctgggtgcgggtgcgttcggtaaagttgttgaagcgaccgcgtacggtctgatcaaatct L  G  A  G  A  F  G  K  V  V  E  A  T  A  Y  G  L  I  K  Sgacgcggcgatgaccgttgcggttaaaatgctgaaaccgtctgcgcacctgaccgaacgt D  A  A  M  T  V  A  V  K  M  L  K  P  S  A  H  L  T  E  Rgaagcgctgatgtctgaactgaaagttctgtcttacctgggtaaccacatgaacatcgtt E  A  L  M  S  E  L  K  V  L  S  Y  L  G  N  H  M  N  I  Vaacctgctgggtgcgtgcaccatcggtggtccgaccctggttatcaccgaatactgctgc N  L  L  G  A  C  T  I  G  G  P  T  L  V  I  T  E  Y  C  Ctacggtgacctgctgaacttcctgcgtcgtaaacgtgactctttcatctgctctaaacag Y  G  D  L  L  N  F  L  R  R  K  R  D  S  F  I  C  S  K  Qgaagaccacgcggaagcggcgctgtacaaaaacctgctgcactctaaagaatcttcttgc E  D  H  A  E  A  A  L  Y  K  N  L  L  H  S  K  E  S  S  Ctctgactctaccaacgaatacatggacatgaaaccgggtgtttcttacgttgttccgacc S  D  S  T  N  E  Y  M  D  M  K  P  G  V  S  Y  V  V  P  Taaagcggacaaacgtcgttctgttcgtatcggttcttacatcgaacgtgacgttaccccg K  A  D  K  R  R  S  V  R  I  G  S  Y  I  E  R  D  V  T  Pgcgatcatggaagacgacgaactggcgctggacctggaagacctgctgtctttctcttac A  I  M  E  D  D  E  L  A  L  D  L  E  D  L  L  S  F  S  Ycaggttgcgaaaggtatggcgttcctggcgtctaaaaactgcatccaccgtgacctggcg Q  V  A  K  G  M  A  F  L  A  S  K  N  C  I  H  R  D  L  Agcgcgtaacatcctgctgacccacggtcgtatcaccaaaatctgcgacttcggtctggcg A  R  N  I  L  L  T  H  G  R  I  T  K  I  C  D  F  G  L  Acgtgacatcaaaaacgactctaactacgttgttaaaggtaacgcgcgtctgccggttaaa R  D  I  K  N  D  S  N  Y  V  V  K  G  N  A  R  L  P  V  Ktggatggcgccggaatctatcttcaactgcgtttacaccttcgaatctgacgtttggtct W  M  A  P  E  S  I  F  N  C  V  Y  T  F  E  S  D  V  W  Stacggtatcttcctgtgggaactgttctctctgggttcttctccgtacccgggtatgccg Y  G  I  F  L  W  E  L  F  S  L  G  S  S  P  Y  P  G  M  Pgttgactctaaattctacaaaatgatcaaagaaggtttccgtatgctgtctccggaacac V  D  S  K  F  Y  K  M  I  K  E  G  F  R  M  L  S  P  E  Hgcgccggcggaaatgtacgacatcatgaaaacctgctgggacgcggacccgctgaaacgt A  P  A  E  M  Y  D  I  M  K  T  C  W  D  A  D  P  L  K  Rccgaccttcaaacagatcgttcagctgatcgaaaaacagatctctgaatctaccaaccac P  T  F  K  Q  I  V  Q  L  I  E  Q  Q  I  S  E  S  T  N  Hatctactctaacctggcgaactgctctccgaaccgtcagaaatagtcgactgaaaaagga I  Y  S  N  L  A  N  C  S  P  N  R  Q  K  - (SEQ ID NO:_)agagt                                        (SEQ ID NO:_)

Met PCR primers MET G1056 CATCCTACATATGGGGGACTCTGATATATCCAGTC 1223(SEQ ID NO:_) G-1364 CTAGCAGGTCGACTACCCAATGAAAGTAGAAGATCGC 1318(SEQ ID NO:_) P1818.pETN6 BI-PTP MET G1056-G1364-X WTtaatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggtcaccaccatcaccatcatatgggggac                            M  G  H  H  H  H  H  H  M  G  Dtctgatatatccagtccattactgcaaaatactgtccacattgacctcagtgctctaaat S  D  I  S  S  P  L  L  Q  N  T  V  H  I  D  L  S  A  L  Nccagagctggtccaggcagtgcagcatgtagtgattgggcccagtagcctgattgtgcat P  E  L  V  Q  A  V  Q  H  V  V  I  G  P  S  S  L  I  V  Httcaatgaagtcataggaagagggcattttggttgtgtatatcatgggactttgttggac F  N  E  V  I  G  R  G  H  F  G  C  V  Y  H  G  T  L  L  Daatgatggcaagaaaattcactgtgctgtgaaatccttgaacagaatcactgacatagga N  D  G  K  K  I  H  C  A  V  K  S  L  N  R  I  T  D  I  Ggaagtttcccaatttctgaccgagggaatcatcatgaaagattttagtcatcccaatgtc E  V  S  Q  F  L  T  E  G  I  I  M  K  D  F  S  H  P  N  Vctctcgctcctgggaatctgcctgcgaagtgaagggtctccgctggtggtcctaccatac L  S  L  L  G  I  C  L  R  S  E  G  S  P  L  V  V  L  P  Yatgaaacatggagatcttcgaaatttcattcgaaatgagactcataatccaactgtaaaa M  K  H  G  D  L  R  N  F  I  R  N  E  T  H  N  P  T  V  Kgatcttattggctttggtcttcaagtagccaaaggcatgaaatatcttgcaagcaaaaag D  L  I  G  E  G  L  Q  V  A  K  G  M  K  Y  L  A  S  K  Ktttgtccacagagacttggctgcaagaaactgtatgctggatgaaaaattcacagtcaag F  V  H  R  D  L  A  A  R  N  C  M  L  D  E  K  F  T  V  Kgttgctgattttggtcttgccagagacatgtatgataaagaatactatagtgtacacaac V  A  D  F  G  L  A  R  D  M  Y  D  K  E  Y  Y  S  V  H  Naaaacaggtgcaaagctgccagtgaagtggatggctttggaaagtctgcaaactcaaaag K  T  G  A  K  L  P  V  K  W  M  A  L  E  S  L  Q  T  Q  Ktttaccaccaagtcagatgtgtggtcctttggcgtgctcctctgggagctgatgacaaga F  T  T  K  S  D  V  W  S  F  G  V  L  L  W  E  L  M  T  Rggagccccaccttatcctgatgtaaacacctttgatataactgtttacttgttgcaaggg G  A  P  P  Y  P  D  V  N  T  F  D  I  T  V  Y  L  L  Q  Gagaagactcctacaacccgaatactgcccagaccccttatatgaagtaatgctaaaatgc R  R  L  L  Q  P  E  Y  C  P  D  P  L  Y  E  V  M  L  K  Ctggcaccctaaagccgaaatgcgcccatccttttctgaactggtgtcccggatatcagcg W  H  P  K  A  E  M  R  P  S  F  S  E  L  V  S  R  I  S  Aatcttctctactttcattgggtagtcgac (SEQ ID NO:_) I  F  S  T  F  I  G  -       (SEQ ID NO:_)

p38 PCR primers p38A P38A-S CGGATCCATATGTCAGGAGAGGCCCAC 253(SEQ ID NO:_) P38A-A GAAACCCTCGAGTCAGGACTCCATCTCTTCTTG 254 (SEQ ID NO:_)P4292.pET15S P3SA M1-S360-X MKK6DDtaatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggcagcagccatcatcatcatcatcacagc                            M  G  S  S  H  H  H  H  H  H  Sagcggcctggtgccgcgcggcagccatatgtctcaggagaggcccacgttctaccggcag S  G  L  V  P  R  G  S  H  M  S  Q  E  R  P  T  F  Y  R  Qgagctgaacaagacaatctgggaggtgcccgagcgttaccagaacctgtctccagtgggc E  L  N  K  T  I  W  E  V  P  E  R  Y  Q  N  L  S  P  V  Gtctggcgcctatggctctgtgtgtgctgcttttgacacaaaaacggggttacgtgtggca S  G  A  Y  G  S  V  C  A  A  F  D  T  K  T  G  L  R  V  Agtgaagaagctctccagaccatttcagtccatcattcatgcgaaaagaacctacagagaa V  K  K  L  S  R  P  F  Q  S  I  I  H  A  K  R  T  Y  R  Ectgcggttacttaaacacatgaaacatgaaaatgtgattggtctgttggacgtttttaca L  R  L  L  K  H  M  K  H  E  N  V  I  G  L  L  D  V  F  Tcctgcaaggtctctggaggaattcaatgatgtgtatctggtgacccatctcatgggggca P  A  R  S  L  E  E  F  N  D  V  Y  L  V  T  H  L  M  G  Agatctgaacaacattgtgaaatgtcagaagcttacagatgaccatgttcagttccttatc D  L  N  N  I  V  K  C  Q  K  L  T  D  D  H  V  Q  F  L  Itaccaaattctccgaggtctaaagtatatacattcagctgacataattcacagggaccta Y  Q  I  L  R  G  L  K  Y  I  H  S  A  D  I  I  H  R  D  Laaacctagtaatctagctgtgaatgaagactgtgagctgaagattctggattttggactg K  P  S  N  L  A  V  N  E  D  C  E  L  K  I  L  D  F  G  Lgctcggcacacagatgatgaaatgacaggctacgtggccactaggtggtacagggctcct A  R  H  T  D  D  E  M  T  G  Y  V  A  T  R  W  Y  R  A  Pgagatcatgctgaactggatgcattacaaccagacagttgatatttggtcagtgggatgc E  I  M  L  N  W  M  H  Y  N  Q  T  V  D  I  W  S  V  G  Cataatggccgagctgttgactggaagaacattgtttcctggtacagaccatattgatcag I  M  A  E  L  L  T  G  R  T  L  F  P  G  T  D  H  I  D  Qttgaagctcattttaagactcgttggaaccccaggggctgagcttttgaagaaaatctcc L  K  L  I  L  R  E  V  O  T  P  G  A  E  L  L  K  K  I  Stcagagtctgcaagaaactatattcagtctttgactcagatgccgaagatgaactttgcg S  E  S  A  R  N  Y  I  Q  S  L  T  Q  M  P  K  M  N  F  Aaatgtatttattggtgccaatcccctggctgtcgacttgctggagaagatgcttgtattg N  V  F  I  G  A  N  P  L  A  V  D  L  L  E  K  M  A  V  Lgactcagataagagaattacagcggcccaagcccttgcacatgcctactttgctcagtac D  S  D  K  R  I  T  A  A  Q  A  L  A  H  A  Y  F  A  Q  Ycacgatcctgatgatgaaccagtggccgatccttatgatcagtcctttgaaagcagggac H  D  P  D  D  E  P  V  A  D  P  Y  D  Q  S  F  E  S  R  Dctccttatagatgagtggaaaagcctgacctatgatgaagtcatcagctttgtgccacca L  L  I  D  E  W  K  S  L  T  Y  D  E  V  I  S  F  V  P  Pccccttgaccaagaagagatggagtcctgactcgac (SEQ ID NO:_) P  L  D  Q  E  D  M  E  S  -        (SEQ ID NO:_)

Pim1 PCR primers PIM1 PIM-1S GCTGGCGCATATGAAGGAGGAGCCCCTGGAG 233(SEQ ID NO:_) PIM-1A GAAAGGGTCGACTTTGCTGGGCCCCGGCGACAG 234 (SEQ ID NO:_)P1215.pET29SRI PIM1 E29-K313 HIS WTagatcgatctcgatcccgcgaaattaatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatatacatatgaaggag                                                    M  K  Eaaggagcccctggagtcgcagtaccaggtgggcccgctactgggcagcggcggcttcggc K  E  P  L  E  S  Q  Y  Q  V  G  P  L  L  G  S  G  G  F  Gtcggtctactcaggcatccgcgtctccgacaacttgccggtggccatcaaacacgtggag S  V  Y  S  G  I  R  V  S  D  N  L  P  V  A  I  K  H  V  Eaaggaccggatttccgactggggagagctgcctaatggcactcgagtgcccatggaagtg K  D  R  I  S  D  W  G  E  L  P  N  G  T  R  V  P  M  E  Vgtcctgctgaagaaggtgagctcgggtttctccggcgtcattaggctcctggactggttc V  L  L  K  K  V  S  S  G  F  S  G  V  I  R  L  L  D  W  Fgagaggcccgacagtttcgtcctgatcctggagaggcccgagccggtgcaagatctcttc E  R  P  D  S  F  V  L  I  L  E  R  P  E  P  V  Q  D  L  Fgacttcatcacggaaaggggagccctgcaagaggagctggcccgcagcttcttctggcag D  F  I  T  E  R  G  A  L  Q  E  E  L  A  R  S  F  F  W  Qgtgctggaggccgtgcggcactgccacaactgcggggtgctccaccgcgacatcaaggac V  L  E  A  V  R  H  C  H  N  C  G  V  L  H  R  D  I  K  Dgaaaacatccttatcgacctcaatcgcggcgagctcaagctcatcgacttcgggtcgggg E  N  I  L  I  D  L  N  R  G  E  L  K  L  I  D  F  G  S  Ggcgctgctcaaggacaccgtctacacggacttcgatgggacccgagtgtatagccctcca A  L  L  K  D  T  V  Y  T  D  F  D  G  T  R  V  Y  S  P  Pgagtggatccgctaccatcgctaccatggcaggtcggcggcagtctggtccctggggatc E  W  I  R  Y  H  R  Y  H  G  R  S  A  A  V  W  S  L  G  Ictgctgtatgatatggtgtgtggagatattcctttcgagcatgacgaagagatcatcagg L  L  Y  D  M  V  C  G  D  I  P  F  E  H  D  E  E  I  I  Rggccaggttttcttcaggcagagggtctcttcagaatgtcagcatctcattagatggtgc G  Q  V  F  F  R  Q  R  V  S  S  E  C  Q  H  L  I  R  W  Cttggccctgagaccatcagataggccaaccttcgaagaaatccagaaccatccatggatg L  A  L  R  P  S  D  R  P  T  F  E  E  I  Q  N  H  P  W  Mcaagatgttctcctgccccaggaaactgctgagatccacctccacagcctgtcgccgggg Q  D  V  L  L  P  Q  E  T  A  E  I  H  L  H  S  L  S  P  Gcccagcaaagtcgaccaccaccaccaccaccactgagatccggctgctaacaaagcccga P  S  K  V  D  H  H  H  H  H  H  -  (SEQ ID NO:_)aaggaattcgagttggctgctgccaccgctgagcaataactagcataaccccttggggcctctaaacgggtcttgaggggttttttg          (SEQ ID NO:_)

Ret PCR primers RET RETH661 GTTCTTCATATGCACAAGTTTGCCCACAACCCA 2184(SEQ ID NO:_) RE-1012-HIS GTTCTTGTCGRCCCTCTTAACCATCATCTTCTCCATCT 2431(SEQ ID NO:_) P1378.pET-SF BI-PTP RET H661-R1012 HIStaatacgactcactataggggaattgtgagcggataacaattcccctotagaaataattttgtttaactttaagaaggagatatacatatgcacaagtttgcccacaagccacccatctcc                            M  H  K  F  A  H  K  P  P  I  Stcagctgagatgaccttccggaggcccgcccaggccttcccggtcagctactcctcttcc S  A  E  M  T  F  R  R  P  A  Q  A  F  P  V  S  Y  S  S  Sggtgcccgccggccctcgctggactccatggagaaccaggtctccgtggatgccttcaag G  A  R  R  P  S  L  D  S  M  E  N  Q  V  S  V  D  A  F  Katcctggaggatccaaagtgggaattccctcggaagaacttggttcttggaaaaactcta I  L  E  D  P  K  W  E  E  P  R  K  N  L  V  L  G  K  T  Lggagaaggcgaatttggaaaagtggtcaaggcaacggccttccatctgaaaggcagagca G  E  G  E  F  G  K  V  V  K  A  T  A  F  H  L  K  G  R  Agggtacaccacggtggccgtgaagatgctgaaagagaacgcctccccgagtgagcttcga G  Y  T  T  V  A  V  K  M  L  K  E  N  A  S  P  S  E  L  Rgacctgctgtcagagttcaacgtcctgaagcaggtcaaccacccacatgtcatcaaattg D  L  L  S  E  E  N  V  L  K  Q  V  N  H  P  H  V  I  K  Ltatggggcctgcagccaggatggcccgctcctcctcatcgtggagtacgccaaatacggc Y  G  A  C  S  Q  D  G  P  L  L  L  I  V  E  Y  A  K  Y  Gtccctgcggggcttcctccgcgagagccgcaaagtggggcctggctacctgggcagtgga S  L  R  G  F  L  R  E  S  R  K  V  G  P  G  Y  L  G  S  Gggcagccgcaactccagctccctggaccaccoggatgagcgggccctcaccatgggcgac G  S  R  N  S  S  S  L  D  H  P  D  E  R  A  L  T  M  G  Dctcatctcatttgcctggcagatctcacaggggatgcagtatctggccgagatgaagctc L  I  S  F  A  W  Q  I  S  Q  G  M  Q  Y  L  A  E  M  K  Lgttcatcgggacttggcagccagaaacatcctggtagctgaggggcggaagatgaagatt V  H  R  D  L  A  A  R  N  I  L  V  A  E  G  R  K  M  K  Itcggatttcggcttgtcccgagatgtttatgaagaggattcctacgtgaagaggagccag S  D  F  G  L  S  R  D  V  Y  E  E  D  S  Y  V  K  R  S  Qggtcggattccagttaaatggatggcaattgaatccctttttgatcatatctacaccacg G  R  I  P  V  K  W  M  A  I  E  S  L  F  D  H  I  Y  T  Tcaaagtgatgtatggtcttttggtgtcctgctgtgggagatcgtgaccctagggggaaac Q  S  D  V  W  S  F  G  V  L  L  W  E  I  V  T  L  G  G  Nccctatcctgggattcctcctgagcggctcttcaaccttctgaagaccggccaccggatg P  Y  P  G  I  P  P  E  R  L  F  N  L  L  K  T  G  H  R  Mgagaggccagacaactgcagcgaggagatgtaccgcctgatgctgcaatgctggaagcag E  R  P  D  N  C  S  E  E  M  Y  R  L  M  L  Q  C  W  K  Qgagccggacaaaaggccggtgtttgcggacatcagcaaagacctggagaagatgatggtt E  P  D  K  R  P  V  F  A  D  I  S  K  D  L  E  K  M  M  Vaagagggtcgaccaccaccaccaccaccactgagatccugctggccctactggccgaaag K  R  V  D  H  H  H  H  H  H  -  (SEQ ID NO:_)gaattcgaggccagcagggccaccgctgagcaataactagcataaccccttggggcctctaaacgggtcttgaggggttttttg          (SEQ ID NO:_)

Src PCR primers SRC-86 GCTGGCCCATATGGTGACACCTTGTGGCCCT 1452(SEQ ID NO:_) SRC-452(L536) CTACTAGTCGACCTAGAGTTCTCCCCGGGCT 1453(SEQ ID NO:_) P1144. pRT-N6 BI-PTP SRC V86-L536-Xtaatacgactcactataggggaattgtgagcggataacaattcccctotagaaataattttgtttaactttaagaaggagatataccatgggtcaccaccatcaccatcatatggtgacc                            M  G  H  H  H  H  H  H  M  V  Tacctttgtggccctctatgactatgagtctaggacggagacagacctgtcottcaagaaa T  F  V  A  L  Y  D  Y  E  S  R  T  E  T  D  L  S  F  K  Kggcgagcggctccagattgtcaacaacacagagggagactggtggctggcccactcgctc G  E  R  L  Q  I  V  N  N  T  E  G  D  W  W  L  A  H  S  Lagcacaggacagacaggctacatccccagcaactacgtggcgccctccgactccatccag S  T  G  Q  T  G  Y  I  P  S  N  Y  V  A  P  S  D  S  I  Qgctgaggagtggtattttggcaagatcaccagacgggagtcagagcggttactgctcaat A  E  E  W  Y  F  G  K  I  T  R  R  E  S  E  R  L  L  L  Ngcagagaacccgagagggaccttcctcgtgcgagaaagtgagaccacgaaaggtgcctac A  E  N  P  R  G  T  F  L  V  R  E  S  E  T  T  K  G  A  Ytgcctctcagtgtctgacttcgacaacgccaagggcctcaacgtgaagcactacaagatc C  L  S  V  S  D  F  D  N  A  K  G  L  N  V  K  H  Y  K  Icgcaagctggacagcggcggcttctacatcacctcccgcacccagttcaacagcctgcag R  K  L  D  S  G  G  F  Y  I  T  S  R  T  Q  F  N  S  L  Qcagctggtggcctactactccaaacacgccgatggcctgtgccaccgcctcaccaccgtg Q  L  V  A  Y  Y  S  K  H  A  D  G  L  C  H  R  L  T  T  Vtgccccacgtccaagccgcagactcagggcctggccaaggatgcctgggagatccctcgg C  P  T  S  K  P  Q  T  Q  G  L  A  K  D  A  W  E  I  P  Rgagtcgctgcggctggaggtcaagctgggccagggctgctttggcgaggtgtggatgggg E  S  L  R  L  E  V  K  L  G  Q  G  C  F  G  E  V  W  M  Gac ctggaacggtaccaccagggtggccatcaaaaccctgaagcctggcacgatgtctcca T  W  N  G  T  T  R  V  A  I  K  T  L  K  P  G  T  M  S  Pgaggccttcctgcaggaggcccaggtcatgaagaagctgaggcatgagaagctggtgcag E  A  F  L  Q  E  A  Q  V  M  K  K  L  R  H  E  K  L  V  Qttgtatgctgtggtttcagaggagcccatttacatcgtcacggagtacatgagcaagggg L  Y  A  V  V  S  E  E  P  I  Y  I  V  T  E  Y  M  S  K  Gagtttgctggactttctcaagggggagacaggcaagtacctgcggctgcctcagctggtg S  L  L  D  F  L  K  G  E  T  G  K  Y  L  R  L  P  Q  L  Vgacatggctgctcagatcgcctcaggcatggcgtacgtggagcggatgaactacgtccac D  M  A  A  Q  I  A  S  G  M  A  Y  V  E  R  M  N  Y  V  Hcgggaccttcgtgcagccaacatcctggtgggagagaacctggtgtgcaaagtggccgac R  D  L  R  A  A  N  I  L  V  G  E  N  L  V  C  K  V  A  Dtttgggctggctcggctcattgaagacaatgagtacacggcgcggcaaggtgccaaattc F  G  L  A  R  L  I  E  D  N  E  Y  T  A  R  Q  G  A  K  Fcccatcaagtggacggctccagaagctgccctctatggccgcttcaccatcaagtcggac P  I  K  W  T  A  P  E  A  A  L  Y  G  R  F  T  I  K  S  Dgtgtggtccttcgggatcctgctgactgagctcaccacaaagggacgggtgccctaccct V  W  S  E  G  I  L  L  T  E  L  T  T  K  G  R  V  P  Y  Pgggatggtgaaccgcgaggtgctggaccaggtggagoggggctaccggatgccctgcccg G  M  V  N  R  E  V  L  D  Q  V  E  R  G  Y  R  M  P  C  Pccggagtgtcccgagtccctgcacgacctcatgtgccagtgctggcggaaggagcctgag P  E  C  P  E  S  L  H  D  L  M  C  Q  C  W  R  K  E  P  Egagcggcccaccttcgagtacctgcaggccttcctggaggactacttcacgtccaccgag E  R  P  T  F  E  Y  L  Q  A  F  L  E  D  Y  F  T  S  T  Eccccagtaccagcccggggagaacctctaggtcgacgaaggagatatatcc (SEQ ID NO:_) P  Q  Y  Q  P  G  E  N  L  -                       (SEQ ID NO:_)

Zap70 PCR primers ZAP70 ZAP70-D327-BAMHI-NAGAGGGATCCGCCACCATGGACAAGAAGCTCTTCCTGAA 5172 (SEQ ID NO:_)ZAP70-G606-HIS ACGAATTCTAGTGGTGGTGGTGGTGGTGGTGCCCTTCCACCT 5171TGCTG (SEQ ID NO:_) P1868.pFastBac1 ZAP70 D327-G606 HIS, WTagatcatggagataattaaaatgataaccatctcgcaaataaataagtattttactgttttcgtaacagttttgtaataaaaaaacctataaatattccggattattcataccgtcccaccatcgggcgcggatccgccaccatggacaagaagctcttcctgaagcgcgataacctcctc                      M  D  K  K  L  F  L  K  R  D  N  L  Latagctgacattgaacttggctgcggcaactttggctcagtgcgccagggcgtgtaccgc I  A  D  I  E  L  G  C  G  N  F  G  S  V  R  Q  G  V  Y  Ratgcgcaagaagcagatcgacgtggccatcaaggtgctgaagcagggcacggagaaggca M  R  K  K  Q  I  D  V  A  I  K  V  L  K  Q  G  T  E  K  Agacacggaagagatgatgcgcgaggcgcagatcatgcaccagctggacaacccctacatc D  T  E  E  M  M  R  E  A  Q  I  M  H  Q  L  D  N  P  Y  Igtgcggctcattggcgtctgccaggccgaggccctcatgctggtcatggagatggctggg V  R  L  I  G  V  C  Q  A  E  A  L  M  L  V  M  E  M  A  Gggcgggccgctgcacaagttcctggtcggcaagagggaggagatccctgtgagcaatgtg G  G  P  L  H  K  F  L  V  G  K  R  E  E  I  P  V  S  N  Vgccgagctgctgcaccaggtgtccatggggatgaagtacctggaggagaagaactttgtg A  E  L  L  H  Q  V  S  M  G  M  K  Y  L  E  E  K  N  F  Vcaccgtgacctggcggcccgcaacgtcctgctggttaaccggcactacgccaagatcagc H  R  D  L  A  A  R  N  V  L  L  V  N  R  H  Y  A  K  I  Sgactttggcctctccaaagcactgggtgccgacgacagctactacactgcccgctcagca D  F  G  L  S  K  A  L  G  A  D  D  S  Y  Y  T  A  R  S  Agggaagtggccgctcaagtggtacgcacccgaatgcatcaacttccgcaagttctccagc G  K  W  P  L  K  W  Y  A  P  E  C  I  N  F  R  K  F  S  Scgcagcgatgtctggagctatggggtcaccatgtgggaggccttgtcctacggccagaag R  S  D  V  W  S  Y  G  V  T  M  W  E  A  L  S  Y  G  Q  Kccctacaagaagatgaaagggccggaggtcatggccttcatcgagcagggcaagcggatg P  Y  K  K  M  K  G  P  E  V  M  A  F  I  E  Q  G  K  R  Mgaatgcccaccagagtgtccacccgaactgtacgcactcatgagtgactgctggatctac E  C  P  P  E  C  P  P  E  L  Y  A  L  M  S  D  C  W  I  Yaagtgggaggatcgccccgacttcctgaccgtggagcagcgcatgcgagcctgttactac K  W  E  D  R  P  D  F  L  T  V  E  Q  R  M  R  A  C  Y  Yagcctggccagcaaggtggaagggcaccaccaccaccaccaccactagaattc (SEQ ID NO:_) S  L  A  S  K  V  E  G  H  H  H  H  H  H  H  -       (SEQ ID NO:_)

BAD substrate PCR primers BAD BAD-N GTTGTCACATATGT7CCAGATCCCAGAGTTTG1613 (SEQ ID NO:_) BAS-S GTTGTGAGTCGACTCACTGGGGAGGGGGCGGA 1614(SEQ ID NO:_) P963.pET-BH BAD M1-Q168-Xtacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatggctggttgcctgaacgacatcttcgaagctcag                         M  A  G  C  L  N  D  I  F  E  A  Qaaaatcgaatggcaccatcaccatcaccatatgttccagatcccagagtttgagccgagt K  I  E  W  H  H  H  H  H  H  M  F  Q  I  P  E  F  E  P  Sgagcaggaagactccagctctgcagagaggggcctgggccccagccccgcaggggacggg E  Q  E  D  S  S  S  A  E  R  G  L  G  P  S  P  A  G  D  Gccctcaggctccggcaagcatcatcgccaggccccaggcctcctgtgggacgccagtcac P  S  G  S  G  K  H  H  R  Q  A  P  G  L  L  W  D  A  S  Hcagcaggagcagccaaccagcagcagccatcatggaggcgctggggctgtggagatccgg Q  Q  E  Q  P  T  S  S  S  H  H  G  G  A  G  A  V  E  I  Ragtcgccacagctcctaccccgcggggacggaggacgacgaagggatgggggaggagccc S  R  H  S  S  Y  P  A  G  T  E  D  D  E  G  M  G  E  E  Pagcccctttcggggccgctcgcgctcggcgccccccaacctctgggcagcacagcgctat S  P  F  R  G  R  S  R  S  A  P  P  N  L  W  A  A  Q  R  Yggccgcgagctcoggaggatgagtgacgagtttgtggactcctttaagaagggacttcct G  R  E  L  R  R  M  S  D  E  F  V  D  S  F  K  K  G  L  Pcgcccgaagagcgcgggcacagcaacgcagatgcggcaaagctccagctggacgcgagtc R  P  K  S  A  G  T  A  T  Q  M  R  Q  S  S  S  W  T  R  Vttccagtcctggtgggatcggaacttgggcaggggaagctccgccccctcccagtgagtc F  Q  S  W  W  D  R  N  L  G  R  G  S  S  A  P  S  Q  -gaccaccaccaccaccaccactgagatccggctggccctactggccgaaaggaattcgaggccagcagggccaccgctgagcaataactagcataaccccttggggcctctaaacgggtcttgaggggttttttg (SEQ ID NO:_) (polypeptide SEQ ID NO:_)

MEK1 substrate PCR primers MEK1 MEK1-S CGGGTCCCATATGCCCAAGAACCCGAC  755(SEQ ID NO:_) MEK-HIS GTTCGTTGTCGACGACGCCAGCAGCATGGGTTG (SEQ ID NO:_)2127 K97A-1 (K104A) CTAATTCATCTGGAGATCGCCCCCGCAATCCGG (SEQ ID NO:_) 2023K97A-2 (K104A) CCGGATTGCGGGCGCGATCTCCAGATGAATTAG (SEQ ID NO:_) 2024P1277.pGEX-BIO MEK1 K97Aatgtcccctatactaggttattggaaaattaagggccttgtgcaacccactcgacttctt M  S  P  I  L  G  Y  W  K  I  K  G  L  V  Q  P  T  R  L  Lttggaatatcttgaagaaaaatatgaagagcatttgtatgagcgcgatgaaggtgataaa L  E  Y  L  E  E  K  Y  E  E  H  L  Y  E  R  D  E  G  D  Ktggcgaaacaaaaagtttgaattgggtttggagtttcccaatcttccttattatattgat W  R  N  K  K  F  E  L  G  L  E  F  P  N  L  P  Y  Y  I  Dggtgatgttaaattaacacagtctatggccatcatacgttatatagctgacaagcacaac G  D  V  K  L  T  Q  S  M  A  I  I  R  Y  I  A  D  K  H  Natgttgggtggttgtccaaaagagcgtgcagagatttcaatgcttgaaggagcggttttg M  L  G  G  C  P  K  E  R  A  E  I  S  M  L  E  G  A  V  Lgatattagatacggtgtttcgagaattgcatatagtaaagactttgaaactctcaaagtt D  I  R  Y  G  V  S  R  I  A  Y  S  K  D  F  E  T  L  K  Vgattttcttagcaagctacctgaaatgctgaaaatgttcgaagatcgtttatgtcataaa D  F  L  S  K  L  P  E  M  L  K  M  F  E  D  R  L  C  H  Kacatatttaaatggtgatcatgtaacccatcctgacttcatgttgtatgacgctcttgat T  Y  L  N  G  D  H  V  T  H  P  D  F  M  L  Y  D  A  L  Dgttgttttatacatggacccaatgtgcctggatgcgttcccaaaattagtttgttttaaa V  V  L  Y  M  D  P  M  C  L  D  A  F  P  K  L  V  C  F  Kaaacgtattgaagctatcccacaaattgataagtacttgaaatccagcaagtatatagca K  R  I  E  A  I  P  Q  I  D  K  Y  L  K  S  S  K  Y  I  Atggcctttgcagggctggcaagccacgtttggtggtggcgaccatcctccaaaatcggat W  P  L  Q  G  W  Q  A  T  F  G  G  G  D  H  P  P  K  S  Dctggttccgcgtggatctcatatgcccaagaagaagccgacgcccatccagctgaacccg L  V  P  R  G  S  H  M  P  K  K  K  P  T  P  I  Q  L  N  Pgcccccgacggctctgcagttaacgggaccagctctgcggagaccaacttggaggccttg A  P  D  G  S  A  V  N  G  T  S  S  A  E  T  N  L  E  A  Lcagaagaagctggaggagctagagcttgatgagcagcagcgaaagcgccttgaggccttt Q  K  K  L  E  E  L  E  L  D  E  Q  Q  R  K  R  L  E  A  Fcttacccagaagcagaaggtgggagaactgaaggatgacgactttgagaagatcagtgag L  T  Q  K  Q  K  V  G  E  L  K  D  D  D  F  E  K  I  S  Ectgggggctggcaatggcggtgtggtgttcaaggtctcccacaagccttctggcctggtc L  G  A  G  N  G  G  V  V  E  K  V  S  H  K  P  S  G  L  Vatggccagagcgctaattcatctggagatcaaacccgcaatccggaaccagatcataagg M  A  R  A  L  I  H  L  E  I  K  P  A  I  R  N  Q  I  I  Rgagctgcaggttctgcatgagtgcaactctccgtacatcgtgggcttctatggtgcgttc E  L  Q  V  L  H  E  C  N  S  P  Y  I  V  G  F  Y  G  A  Ftacagcgatggcgagatcagtatctgcatggagcacatggatggaggttctctggatcaa Y  S  D  G  E  I  S  I  C  M  E  H  M  D  G  G  S  L  D  Qgtcctgaagaaagctggaagaattcctgaacaaattttaggaaaagttagcattgctgta V  L  K  K  A  G  R  I  P  E  Q  I  L  G  K  V  S  I  A  Vataaaaggcctgacatatctgagggagaagcacaagatcatgcacagagatgtcaagccc I  K  G  L  T  Y  L  R  E  K  K  I  M  M  H  R  D  V  K  Ptccaacatcctagtcaactcccgtggggagatcaagotctgtgactttggggtcagcggg S  N  I  L  V  N  S  R  G  E  I  K  L  C  D  F  G  V  S  Gcagctcatcgactccatggccaactccttcgtgggcacaaggtcctacatgtcgccagaa Q  L  I  D  S  M  A  N  S  E  V  G  T  R  S  Y  M  S  P  Eagactccaggggactcattactctgtgcagtcagacatctggagcatgggactgtctctg R  L  Q  G  T  H  Y  S  V  Q  S  D  I  W  S  M  G  L  S  Lgtagagatggcggttgggaggtatcccatccctcctccagatgccaaggagctggagctg V  E  M  A  V  G  R  Y  P  I  P  P  P  D  A  K  E  L  E  Latgtttgggtgccaggtggaaggagatgcggctgagaccccacccaggccaaggaccccc M  F  G  C  Q  V  E  G  D  A  A  E  T  P  P  R  P  R  T  Pgggaggccccttagctcatacggaatggacagccgacctcccatggcaatttttgagttg G  R  P  L  S  S  Y  G  M  D  S  R  P  P  M  A  I  F  E  Lttggattacatagtcaacgagcctcctccaaaactgcccagtggagtgttcagtctggaa L  D  Y  I  V  N  E  P  P  P  K  L  P  S  G  V  F  S  L  Etttcaagattttgtgaataaatgcttaataaaaaaccccgcagagagagcagatttgaag F  Q  D  F  V  N  K  C  L  I  K  N  P  A  E  R  A  D  L  Kcaactcatggttcatgcttttatcaagagatctgatgctgaggaagtggattttgcaggt Q  L  M  V  H  A  F  I  K  R  S  D  A  E  E  V  D  F  A  Gtggctctgctccaccatcggccttaaccagcccagcacaccaacccatgctgctggcgtc W  L  C  S  T  I  G  L  N  Q  P  S  T  P  T  H  A  A  G  Vgtcgacctgaacgacatcttcgaagctcagaaaatcgaatggcaccgttagaattc V  D  L  N  D  I  F  E  A  Q  K  I  E  W  H  R  - (SEQ ID NO:_)(nucleic acid SEQ ID NO:_)

Example 76 Efficacy of Compounds in Combination with Standard-of-CareChemotherapeutic Agents in Four Human Cancer Cell Lines

Compounds of the invention, such as compounds of Formula III, incombination with a standard chemotherapeutic agent, such as5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, or vinblastine, can be assessed fortheir effectiveness in killing human tumor cells. Human tumor celllines, such as A-375 (malignant melanoma), SK-MEL-2 (malignant melanoma,skin metastasis), COLO 205 (colorectal adenocarcinoma, ascitesmetastasis) or SW-620 (colorectal adenocarcinoma, lymph node metastasis)can be treated with a compound of Formula III alone, or in combinationwith one of the above-mentioned chemotherapeutic agents.

Tumor cells are grown as a monolayer at 37° C. in a humidifiedatmosphere (5% COs, 95% air). Cells are grown in a suitable culturemedium, e.g. RPMI 1640 (Ref BE12-702F, Cambrex, Verviers, Belgium)containing 2 mM L-glutamine and supplemented with 10% fetal bovine serum(Ref DE14-801E, Cambrex). For experimental use, the tumor cells aredetached from the culture flask by a 5-minute treatment withtrypsin-versene (Ref 2-007E, Cambrex), diluted in Hanks' medium withoutcalcium or magnesium (Ref BE10-543F, Cambrex). Trypsin treatment isneutralized by culture medium addition. The cells are counted in ahemocytometer and their viability assessed by 0.25% trypan blueexclusion.

The cell lines are checked for mycoplasma contamination with theMycotect assay kit (Ref 15672-017, Invitrogen, Cergy-Pontoise, France)in accordance with the manufacturer's instructions. The mycoplasma testis assayed from the culture supernatants of the cell lines and comparedto negative and positive controls.

The tumor cells (10,000 per well) are plated in 96-well flat-bottommicrotitration plates (Ref 055260, Nunc, Dutscher, Brumath, France) andincubated at 37° C. for 24 hours before treatment in 100 μl of drug-freeculture medium supplemented with 10% FBS. In order to assess the IC₅₀ ofeach compound to be used for each cell line, the tumor cells areincubated in a 200 μl final volume of RPMI 1640 supplemented with 10%FBS and containing either a compound of Formula III or one of5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, or vinblastine. The compounds aretested in a suitable concentration range, such as 10⁻⁸ to 10⁻³ M for acompound of Formula III, 5-fluorouracil, dacarbazine or gefitinib, 10⁻⁹to 10⁻⁴ M for carboplatin, oxaliplatin, or temozolomide, 10⁻¹ to 10⁻⁶ Mfor paclitaxel or SN-38, and 10⁻¹⁵ to 10⁻³ M for vinblastine. Compoundsof Formula III are dissolved in DMSO and diluted with culture medium tothe desired concentrations. 5-fluorouracil (50 mg/ml, Dakota Pharm,LePlessis Robinson, France), carboplatin (10 mg/ml, Aguettant, Lyon,France), and paclitaxel (6 mg/ml, Bristol-Myers Squibb SpA, RueilMalmaison, France), are diluted with culture medium to the desiredconcentrations. Dacarbazine (Sigma, Saint Quentin Fallavier, France) andvinblastine (Lilly France S.A., Saint Cloud, France) are dissolved inNaCl 0.9% and diluted with culture medium to the desired concentrations.Gefitinib is dissolved in a mixed solution of RPMI 1640 and DMSO anddiluted with culture medium to the desired concentrations (maximum finalDMSO of 0.1% v/v). SN-38 (LKT Laboratories, Inc., St. Paul, Minn.) isdissolved in DMSO and diluted with culture medium to the desiredconcentrations (maximum final DMSO of 0.1% v/v). Temozolomide (LKTLaboratories, Inc., St. Paul, Minn.) is dissolved in water for injectionand diluted with culture medium to the desired concentrations. Cells areincubated for 96 hours in the presence of test substances at 37° C.under 5% CO₂. At the end of treatments, the cytotoxic activity isevaluated by an MTT assay.

For the MT assay, at the end of the cells treatment, 20 μl of a 5 mg/mlsolution 0.22 μm filtered tetrazolium reagent (MTT, Ref M2128, Sigma) inPhosphate Buffered Saline (PBS, Ref BE17-517Q, Cambrex), is added ineach well, Culture plates are incubated for 2 h at 37° C. The resultingsupernatant is removed and formazan crystals dissolved with 200 μl ofDMSO per well. Absorbency (OD) is measured at 570 nm in each well usingVICTOR³™ 1420 multilabeled counter (Wallac, PerkinElmer, Courtaboeuf,France).

The ICs₅₀ for each compound on each cell line is determined from the ODmeasurements of each sample. The dose response inhibition of cellproliferation is expressed as:

IC=(OD of drug exposed cells/OD of drug free wells)×100.

The mean of multiple measurements for each concentration is plotted vs.the drug concentration. The dose-response curves are plotted using XLFit3 (IDBS, United Kingdom). The IC₅₀ (drug concentration to obtain 50%inhibition of cell proliferation) determination values are calculatedusing the XLFit 3 from semi-log curves. The IC₅₀ value determined foreach compound in each cell line is used to determine the concentrationof a compound of Formula III and of the standard chemotherapeutic to beused in combination.

The cells are treated with a combination of five concentrations of acompound of Formula III and five concentrations of one of5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, or vinblastine, based on the IC₅₀results. The compounds and cells are treated per the IC50 determinationdescribed above and assayed by the MTT assay.

The results are assessed to determine whether the combination issynergistic or antagonistic. The compound interactions are calculated bymultiple drug effect analysis and are performed by the median equationprinciple according to the methodology described by Chou and Talalay(Adv. Enzyme Regul. 1984, 22: 27-55).

The combination index (CI) will be calculated by the Chou et al,equation (Adv. Enzyme Regul. 1984, 22: 27-55; Encyclopaedia of humanbiology, Academic Press, 1991, 2: 371-9; Synergism and Antagonism inChemotherapy, Academic Press, 1991, 61-102) which takes into accountboth the potency (D_(m) or IC₅₀) and the shape of the dose-effect curve(the m value). The general equation for the CI of the two compounds isgiven by:

${CI} = {\frac{(D)_{1}}{\left( D_{x} \right)_{1}} + \frac{(D)_{2}}{\left( D_{x} \right)_{2}} + \frac{(D)_{1}(D)_{2}}{\left( D_{x} \right)_{1}\left( D_{x} \right)_{2}}}$

where:(D_(x))₁ and (D_(x))₂ in the denominators are the doses (orconcentrations) for compound 1 and compound 2 alone which demonstrate x% of inhibition, whereas (D)₁ and (D)₂ in the numerators are doses ofboth compounds (1 and 2) in combination that also inhibit x %(iso-effective). CI<1, =1, and >1 indicate synergism, additive effectand antagonism, respectively.

The (D_(x))₁ and (D_(x))₂ can be calculated from the median-effectequation of Chou et al. (J. Natl. Cancer Inst. 1994, 86: 1517-24):

$D_{x} = {D_{m}\left( \frac{f_{a}}{\left( {1 - f_{a}} \right)} \right)}^{1\text{/}m}$

where:D_(m) is the median-effect dose that is obtained from the anti-log ofx-intercept of the median-effect plot, x=log(D) versus y=log{/(f_(a)/(1−f)}, or D_(m)=10^(−(y-intercept)/m); and m is the slope ofthe median-effect plot and f_(a) is the fraction of cells affected bythe treatment. Each CI will be calculated with CalcuSyn software(Biosoft, UK) from the mean affected fraction at each drug ratioconcentration.

Additional Examples

Unless specifically indicated otherwise, the Formula enumeration and Rgroup enumeration used in the following examples is not related to suchenumeration in other sections of this application. The reagents andsolvents used in these examples can be readily substituted withappropriate alternatives as are known in the art and isolation ofproducts is readily achieved by methods known in the art, including, butnot limited to, extraction, crystallization, and chromatographicmethods. For the following examples, the following formulae are defined:

wherein:

-   -   R⁴ and R⁵ are as defined in paragraph [10008];    -   R¹², R¹³ and R¹⁶ are as defined in paragraph [0103];    -   R²⁸ is —SO₂R²⁵, —C(═O)R²⁵, —C(═O)NR²⁵, —C(═O)OR²⁵, —C(═S)R²⁵,        —C(═S)NR²⁵, —C(═S)OR²⁵, or —SO₂NR²⁵R²⁶; wherein R²⁵ and R²⁶ are        hydrogen, optionally substituted lower alkyl, optionally        substituted lower alkenyl, optionally substituted lower alkynyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, or optionally        substituted heteroaryl, or    -   R²⁵ and R²⁶ together with the nitrogen form optionally        substituted 5-7 membered heterocycloalkyl or optionally        substituted 5 or 7 membered nitrogen containing heteroaryl    -   R²⁹ is hydrogen or optionally substituted lower alkyl; and    -   R³⁰ is optionally substituted lower alkyl or optionally        substituted benzyl, wherein optionally substituted benzyl refers        to an optionally substituted aralkyl with unsubstituted        structure —CH₂-phenyl.

Example 77 Synthesis of Compound of Formula II, where R¹² and R¹⁶ areIndependently fluoro or chloro

Step 1—Synthesis of Compound of Formula II

Compound of Formula II, where R¹² and R¹⁶ are fluoro or chloro, may besynthesized by reacting a compound of Formula III with an organolithiumreagent (e.g. n-butyllithium, lithium diisopropylamine) in an inertsolvent (e.g. THF), followed by the addition of a formylating reagent(e.g. DMF). The reaction is allowed to proceed, typically at −78° C.,for 1-2 hours and the desired product is isolated by standard procedures(e.g. extraction, silica gel chromatography).

Example 78 Synthesis of Compound of Formula III, where R¹³ is NR²⁸R²⁹

Step-1—Synthesis of Compound of Formula III where R¹³ is NR²⁸R²⁹

Compound of Formula III, where R¹³ is NR²⁸R²⁹, may be synthesized byreacting a compound of Formula IV with a base (e.g. pyridine, sodiumhydride) in an inert solvent (e.g. DMF, CH₂Cl₂), followed by anappropriate reagent (R²⁵SO₂Cl, e.g. propane-1-sulfonyl chloride;R²⁵C(═O)Cl, e.g. acetyl chloride; R²⁵NCO, e.g. propyl isocyanate;R²⁵OC(═O)Cl, e.g. benzyl chloroformate; R³⁶R²⁵NSO₂Cl, e.g.dimethylsulfamoyl chloride.) The reaction is allowed to proceed,typically at room temperature, for 8-12 hours and the desired product isisolated by standard procedures (e.g. extraction and silica gelchromatography).

Example 79 Synthesis of Compound of Formula III, where R¹³ is CONR²⁵R²⁶

Step-1—Synthesis of Compound of Formula III, where R¹³ is C(═O)NR²⁵R²⁶

Compound of Formula III, where R¹³ is C(═O)NR²⁵R²⁶, may be synthesizedby reacting a compound of Formula V with a base (e.g.N,N-diisopropylethylamine) and condensing reagents (e.g.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole) in an inert solvent (e.g. tetrahydrofuran),followed by an amine (R²⁵R²⁶NH, e.g. 1-propanamine). The reaction isallowed to proceed, typically at room temperature, for 8-12 hours andthe desired product is isolated by standard procedures (e.g. extraction,silica gel chromatography).

Example 80 Synthesis of Compound of Formula III, where R¹³ is SO₂NR²⁵R²⁶

Step-1—Synthesis of Compound of Formula III

Compound of Formula III, where R¹³ is —SO₂NR²⁵R²⁶, is synthesized byreacting a compound of Formula VI with a base (e.g. triethylamine) in aninert solvent (e.g. CH₂Cl₂), followed by an appropriate reagent(R²⁵R²⁵NH₂, e.g. 1-propanamine). The reaction is allowed to proceed,typically at room temperature, for 2-5 hours and the desired product isisolated by standard procedures (e.g. extraction, silica gelchromatography).

Example 81 Synthesis of Compound of Formula III, where R¹³ is OP where Pis a Protecting Group

Step-1—Synthesis of Compound of Formula III, where R¹³ is OP and P is aprotecting group

Compound of Formula III, where R¹³ is —OP and P is a protecting group,is synthesized by reacting a compound of Formula VII with a base (e.g.imidazole) in a polar solvent (e.g. DMF), followed by an appropriatereagent (e.g. tert-butyl-chloro-dimethyl-silane) to introduce theprotecting group. The reaction is allowed to proceed, typically at roomtemperature, for 8-12 hours, and the desired product is isolated bystandard procedures (e.g. extraction, silica gel chromatography).

Example 82 Synthesis of Compound of Formula VIII

Step-1—Synthesis of Compound of Formula VII

Compound of Formula VIII is synthesized by reacting a compound ofFormula IX with a base (e.g. pyridine) in an inert solvent (e.g.CH₂Cl₂), followed by sulfuryl chloride. The reaction is allowed toproceed, typically under reflux, for 8-12 hours and the desired productis isolated by standard procedures (e.g. evaporation).

Example 83 Synthesis of Compounds of Formula X

Step 1—Preparation of Compounds of Formula XIIa and XIIb

To a compound of Formula XVIII and a compound of Formula II is added anappropriate solvent (e.g. methanol) followed by an appropriate base(e.g. potassium hydroxide, sodium methoxide). The reaction is typicallyallowed to stir at room temperature overnight. Isolation by conventionmeans (e.g. extraction, washing and filtering) affords a mixture ofcompounds of Formula XIIa and XIIb which may be separated by silica gelchromatography if desired.

Step 2—Preparation of Compounds of Formula X

To a compound of Formula XIIa or XIIb in an appropriate solvent (e.g.acetonitrile) is added a reducing agent (e.g. trifluoroacetic acid andtriethylsilane). Typically, the reaction is allowed to stir at roomtemperature overnight. Isolation by conventional means (e.g. extractionand silica gel column chromatography) affords compounds of Formula X.

Example 84 Synthesis of Compounds of Formula I

Step 1—Preparation of Compounds of Formula I

To a compound of Formula XIIa in an appropriate solvent (e.g. THF) isadded an oxidizing agent (e.g. Dess-Martin periodane, TEMPO, DDQ).Typically, the reaction is allowed to stir at room temperature for 20minutes. Isolation by conventional means (e.g. extraction and silica gelcolumn chromatography) affords compounds of Formula I.

Example 85 Synthesis of Compounds of Formula XIII where R¹² and R¹⁶ areIndependently chloro or fluoro

Step-1—Synthesis of Compound of Formula XIII, where R¹² and R¹⁶ arechloro or fluoro

Compound of Formula XIII, where R¹² and R¹⁶ are chloro or fluoro, issynthesized by reacting a compound of Formula XIV with an organolithiumreagent (e.g. n-butyllithium) and a temporary protecting group (e.g.1,2-Bis-(chloro-dimethyl-silanyl)-ethane) and DMF in a inert solvent(e.g. THF) under inert atmosphere (e.g. argon) at −78° C. for 2-4 hours,followed by removal of the temporary protecting group using an acid(e.g. 1N HCl). The product is isolated by extraction and silica gelcolumn chromatography.

Example 86 Synthesis of Compounds of Formula XV, where R¹³ is NHR²⁸

Step 1—Synthesis of Compound of Formula XVI

Compound of Formula XVI may be synthesized by reacting a compound ofFormula XIII with a base (e.g. pyridine, sodium hydride) in an inertsolvent (e.g. DMF, CH₂Cl₂), followed by an appropriate reagent(R²⁵SO₂Cl, e.g., propane-1-sulfonyl chloride; R²⁵C(═O)Cl, e.g. acetylchloride; R²NCO, e.g., propyl isocyanate; R²⁵OC(═O)Cl, e.g., benzylchloroformate; R²⁶R²⁵NSO₂Cl, e.g., dimethylsulfamoyl chloride). Thereaction is allowed to proceed, typically at room temperature, for 8-12hours and the desired product is isolated by standard procedures (e.g.extraction and silica gel chromatography).

Step 2—Synthesis of Compound of Formula XVII

Compound of Formula XVII, may be synthesized by hydrolyzing a compoundof Formula XVI with an aqueous base solution (e.g. sodium hydroxide).The reaction is allowed to proceed, typically under reflux, for 8-12hours and the desired product is isolated by standard procedures (e.g.extraction).

Step 3—Synthesis of Compound of Formula XV, where R¹³ is NHR²⁸

Compound of Formula XV, where R¹³ is NHR²⁸, may be synthesized byreacting a compound of Formula XVII with thionyl chloride. The reactionis allowed to proceed, typically under reflux, for 3 hours and thedesired product is isolated by standard procedures (e.g. evaporation).

Example 87 Synthesis of Compounds of Formula XV

Step 1—Synthesis of Compound of Formula XV

Compound of Formula XV may be synthesized by reacting a compound ofFormula XIX with thionyl chloride. The reaction is allowed to proceed,typically under reflux, for 3 hours and the desired product is isolatedby standard procedures (e.g. evaporation).

Example 88 Synthesis of Compounds of Formula I

Step-1—Synthesis of Compound of Formula I

Compound of Formula I is synthesized by reacting a compound of FormulaXVIII with a compound of Formula XV (Example 83, e.g. benzoyl chloride)in the presence of a Lewis acid (e.g. aluminum trichloride) in an inertsolvent (e.g. methylene chloride) under an inert atmosphere (e.g. argon)at room temperature or with heating up to reflux for 1-18 hours. Theproduct is isolated by extraction and silica gel column chromatography.

Example 89 Synthesis of Compounds of Formula I where R⁵ is aryl orheteroaryl

Step 1: Synthesis of Compound of Formula I, where R⁵ is aryl orheteraryl

Compound of the Formula I, where R⁵ is aryl or heteroaryl, is preparedby reacting a compound of Formula I, where R⁵ is bromo, under Suzukicoupling conditions, with boronic acid (e.g. phenyl boronic acid) in thepresence of a base (e.g., potassium carbonate) and catalyst (e.g.,Pd(Ph₃P)₄) in aqueous/THF solvent system. After 4-12 hours with heatingto 80° C. or heating in a microwave instrument at 120° C. for 15minutes, the product is isolated by standard workup procedures (e.g.silica gel column chromatography).

Example 90 Synthesis of Compounds of Formula I

Step-1—Synthesis of Compound XX

Compound of Formula XX can be synthesized by reacting a compound ofFormula XVIII with hexamethyltetramine and acetic acid in water withheating to reflux for two hours. After cooling, the desired productprecipitates and may be collected by filtration.

Step-2—Synthesis of Compound of Formula XXI

Compound of Formula XXI, where P is a protecting group, is synthesizedby reacting a compound XX with an appropriate reagent to introduce aprotecting group (P—X, e.g. triisopropylsilylchloride) and a base (e.g.sodium hydride) in a solvent (e.g. THF) typically at room temperaturefor 8-12 hours. The product is isolated by conventional means (e.g.extraction).

Step-3—Synthesis of Compound of Formula XXII

Compound of Formula XXII is synthesized by reacting a compound ofFormula XXI in a solvent (e.g. THF) with an organolithium reagent (e.g.phenyl lithium) in a solvent (e.g. THF) under an inert atmosphere,cooled to −78° C. An appropriate organolithium reagent can also beprepared by reacting compounds of Formula III, where R¹² and R¹⁶ areindependently fluoro or chloro, with an organolithium reagent (e.g.butyllithium) in a solvent (e.g. THF) under an inert atmosphere, cooledto −78° C. The reaction is typically allowed to warm to room temperatureand stirred for 30 minutes. The product is isolated by conventionalmeans (e.g. extraction).

Step-4—Synthesis of an Intermediate of Compound of Formula I

An intermediate of compound of Formula I is synthesized by reacting acompound of Formula XXII with an appropriate reagent to remove theprotecting group, P, (e.g. tetra-n-butyl ammonium fluoride) in anappropriate solvent (e.g. THF). The final product is isolated bystandard procedures (e.g. extraction).

Step-5—Synthesis of Compound of Formula I

Compound of Formula I is synthesized by reacting the intermediate fromStep 4 with an oxidizing agent (e.g. Dess-Martin periodane, TEMPO) in anaprotic solvent (e.g. THF) typically at room temperature for 20 minutes.The product is isolated by conventional means (e.g. extraction andsilica gel chromatography).

Example 91 Synthesis of Compounds of Formula I, where R¹³ isNHC(═O)NR²⁵R²⁶

Step 1—Preparation of Compounds of Formula XIIa where R¹³ is NHC(═O)OR²⁸

To a compound of Formula XVIII and a compound of Formula II, where R¹³is NHC(═O)OR²⁸, is added an appropriate solvent (e.g. methanol) followedby an appropriate base (e.g. potassium hydroxide). The reaction istypically allowed to stir at room temperature overnight. Isolation byconvention means (e.g. extraction, washing and filtering) affordscompound of Formula XIIa where R¹³ is NHC(═O)OR²⁸.

Step 2—Preparation of Compounds of Formula XIIa, where R¹³ isNHC(═O)NR²⁵R²⁶

Compound of Formula XIIa, where R¹³ is NHC(═O)NR²⁵R²⁶, is synthesized byreacting a compound of Formula XIIa, where R¹³ is NHC(═O)OR²⁸, with anamine of the formula NHR²⁵R²⁶ (e.g. propylamine) in an appropriatesolvent (e.g. dioxane) followed by an appropriate base (e.g.triethylamine). The reaction is typically heated at 140° C. for 15minutes in a CEM Discover microwave instrument. Isolation by conventionmeans (e.g. extraction, washing and filtering) affords compounds ofFormula XIIa, where R¹³ is NHC(═O)NR²⁵R²⁶.

Step 3—Preparation of Compounds of Formula I, where R¹³ isNHC(═O)NR²⁵R²⁶

Compound of Formula I, where R¹³ is NHC(═O)NR²⁵R²⁶, is synthesized byreacting a compound of Formula XIIa, where R¹³ is NHC(═O)NR²⁵R²⁶, withan oxidizing agent (e.g. Dess-Martin periodane, TEMPO) in an appropriatesolvent (e.g. THF). The reaction is typically stirred at roomtemperature for 15 minutes. Isolation by convention means (e.g.extraction, washing and filtering) affords compounds of Formula I, whereR¹³ is NHC(═O)NR²⁵R²⁶.

Example 92 Synthesis of Compounds of Formula I, where R¹³ is NHC(═O)OR²⁵

Step 1—Preparation of Compounds of Formula XIIa, where R¹³ isNHC(═O)OR²⁵

Compound of Formula XIIa, where R¹³ is NHC(═O)OR²⁵, is synthesized byreacting a compound of Formula XIIa, where R¹³ is NHC(═O)OR²⁸, with analcohol of the formula R²⁵OH (e.g. methanol) in an appropriate solvent(e.g. dioxane) followed by an appropriate base (e.g. triethylamine). Thereaction is typically heated at 140° C. for 15 minutes in a CEM Discovermicrowave instrument. Isolation by convention means (e.g. extraction,washing and filtering) affords compounds of Formula XIIa, where R¹³ isNHC(═O)OR²⁵.

Step 2—Preparation of Compounds of Formula I, where R¹³ is NHC(═O)OR²⁵

Compound of Formula I, where R¹³ is NHC(═O)OR²⁵, is synthesized byreacting a compound of Formula XIIa, where R¹³ is NHC(═O)OR²⁵, with anoxidizing agent (e.g. Dess-Martin periodane, TEMPO) in an appropriatesolvent (e.g. THF). The reaction is typically stirred at roomtemperature for 15 minutes. Isolation by convention means (e.g.extraction, washing and filtering) affords compounds of Formula I, whereR¹³ is NHC(═O)OR²⁵.

Example 93 Synthesis of Compounds of Formula I, where R⁴ and R⁵ areHydrogen

Step 1 Preparation of Compounds of Formula I where R⁴ and R⁵ areHydrogen

Compound of Formula I, where R⁴ and R⁵ are hydrogen, is synthesized byhydrogenating compound of Formula I, where R⁴ is hydrogen and R⁵ isbromo, in the presence of an appropriate solvent (e.g methanol) andcatalyst (e.g. 10% Pd/C), under an atmosphere of hydrogen gas. Thereaction is typically allowed to stir at room temperature for 8-12hours. Isolation by convention means (e.g. extraction, washing andfiltering) affords compounds of Formula I, where R⁴ and R⁵ are hydrogen.

Synthesis of Compound of Formula Ia

Compounds of Formula Ia are compounds of Formula XVIII in which R⁴ ishydrogen and R⁵ is the only substituent on the core structure. Exemplarysynthetic schemes for groups of compounds within Formula Ia are shown inExamples 91 to 99 for different selections of R⁵.

Example 94 Synthesis of Compounds of Formula Ia where R⁵ is aryl orheteroaryl

Compound of Formula Ia, where R⁵ is aryl or heteroaryl, is synthesizedfrom compound 1 under Suzuki reaction conditions using aryl orheteroaryl bornonic acids (e.g. phenyl bornonic acid) in the presence ofa base (e.g. potassium carbonate) and a catalyst (e.g. Pd(PPh₃)₄) inaqueous/THF system with thermal heating (e.g. 80° C. for 12 hours) ormicrowave heating (e.g. 120° C. for 15 minutes). The product is isolatedby conventional means (e.g. silica gel column chromatography).

Example 95 Synthesis of Compounds of Formula Ia where R⁵ is a alkyl orcycloalkyl

Step-1—Synthesis of Compound of Formula XXIII

Compound of Formula XXIII, where P is a protecting group, is synthesizedby reacting compound 1 with a base (e.g. sodium hydride) in an inertsolvent (e.g. THF), followed by an appropriate reagent (P—X, e.g.,triisopropylsilylchloride) for introduction of a protecting group. Thereaction is allowed to proceed, typically at room temperature, for 8-12hours and the desired product is isolated by standard procedures (e.g.extraction) (Greene, T. W.; Wuts, P.G.M. Protective Groups in OrganicSynthesis 1, 3^(rd) ed.; John Wiley & Sons: New York, 1981).

Step-2—Synthesis of an Intermediate of Compound of Formula Ia, where R⁵is alkyl and cycloalkyl

An intermediate of compound of Formula Ia, where R⁵ is alkyl orcycloalkyl, is synthesized by reacting a compound of Formula XXIII withan alkyl or cycloalkyl Grignard reagent (e.g. ethyl magnesium bromide)in the presence of catalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) in an inertsolvent (e.g. toluene) at low temperature (e.g. −78° C.) or under refluxfor 2-8 hours. The product is isolated by standard procedures (e.g.extraction and silica gel column chromatography) as described byliterature. (T. Hayashi, M. Konishi, Y. Kobori, M. Kumada, T. Iliguchi,K. Hirotsu; J. Am. Chem. Soc. 1984, 106, 158-163).

Step-3—Synthesis of Compound of Formula Ia, where R⁵ is alkyl andcycloalkyl

Compound of Formula Ia, where R⁵ is alkyl or cycloalkyl, is synthesizedby reacting an intermediate of compound Formula Ia from Step 2 with anappropriate reagent to remove the protecting group (e.g.tetrabutylammonium fluoride) in an appropriate solvent (e.g.tetrahydrofuran). The product is isolated by standard procedures (e.g.extraction and silica gel column chromatography).

Example 96 Synthesis of Compounds of Formula Ia where R⁵ is NR²²R²³

Step-1—Synthesis of an Intermediate of Compound of Formula XXIV

An intermediate of compound of Formula XXIV, is synthesized by reactinga compound of Formula XXIII, with an amine of the formula NHR²²R²³ (e.g.aniline) in a solvent (e.g. toluene), in the presence of a base (e.g.sodium tert-butoxide) and a catalyst composed of a metal (e.g.,Tris(dibenzylideneacetone)dipalladium(0)) and a ligand (e.g.,tri-tert-butylphosphine) with heating, typically to 95° C., for 8-12hours as described (Thomas, et. al., J. Am. Chem. Soc., 2001, 123, 9404)by substituting a compound of Formula XXIII for theN-substituted-3,6-dibromocarbazole. The desired compound is purified bysilica gel column chromatography. This intermediate is used directly inStep 3 to provide compound of Formula Ia where R⁵ is NR²²R²³ and R²² andR²³ are not —C(X)R²⁰, —C(X)NR¹⁷R¹⁸, —S(O)₂R²¹, or S(O)₂NR¹⁷R¹⁸ oralternatively, it can be additionally substituted as described in Step2.

Step-2—Synthesis of Compound of Formula XXIV

The intermediate from Step 1 can be further modified when R²² or R²³ ishydrogen. In this case, the intermediate from Step 1 can be reacted witha base (e.g. sodium hydride) in a solvent (e.g. N,N-dimethylformamide),followed by reaction with an alkylating reagent (e.g. benzyl bromide) oran acylating reagent (e.g. benzoyl chloride, phenyl isocyanate, phenylisothiocyanate, phenylsulfonyl chloride) typically at room temperatureor with heating up to 80° C. for 1-12 hours. The desired product can bepurified by conventional means (e.g. silica gel column chromatography).Alternatively, when R²² or R²³ is a suitable protecting group (e.g.benzyl), it may be removed by appropriate treatment (e.g. hydrogenation)to provide a compound where R²² and/or R²³ are hydrogen, which issuitable for further modification with an alkylating reagent oracylating reagent as described herein.

Step-3—Synthesis of Compound of Formula Ia, where R³ is —NR²²R²³

Compound of Formula Ia, where R⁵ is —NR²²R²³, is synthesized by reactinga compound of Formula XXIV with an appropriate reagent to remove theprotecting group (e.g. tetra-n-butylammonium fluoride) in an appropriatesolvent (e.g. methanol). The final product can be isolated by standardprocedures (e.g. extraction).

Example 97 Synthesis of Compounds of Formula Ia where R⁵ is C(O)NR²⁵R²⁶

Step-1—Synthesis of Compound of Formula XXIII

Compound of Formula XIII, where P is a protecting group, is synthesizedby reacting compound 1 with a base (e.g. sodium hydride) in a solvent(e.g. THF), followed by an appropriate reagent (P—X, e.g.triisopropylsilylchloride) for introduction of a protecting group. Thereaction is allowed to proceed, typically at room temperature for 8-12hours, and the desired product is isolated by standard procedures (e.g.extraction and silica gel column chromatography) (Greene, T. W.; Wuts,P.G.M. Protective Groups in Organic Synthesis 1, 3^(rd) ed.; John Wiley& Sons: New York, 1981).

Step-2—Synthesis of Compound of Formula XXVI

Compound of Formula XXVI may be synthesized by reacting a compound ofFormula XXIII with sodium cyanide in a polar aprotic solvent (e.g. DMF)in an inert atmosphere (e.g. argon), in the presence of a catalyst (e.g.cuprous iodide or Tris(dibenzylideneacetone)dipalladium(0)) followingthe procedure described by Buchwald et. al., J. Am. Chem. Soc., 2003,125, 2890-2891, by substituting 5-bromo-7-azaindole for 5-bromo-indole.

Step-3—Synthesis of Compound of Formula XXVII

Compound of Formula XXVII may be synthesized by heating a compound ofFormula XXVI with aqueous base (e.g. aq. KOH) in the presence of analcohol (e.g. ethanol) at higher temperatures (e.g. 90° C.) for requiredtime, typically 24 h, as described in Org. Syn. Collective Volume 2, 292(1943). Alternatively, compounds of Formula XXVII may be synthesizeddirectly from a compound of Formula XXIII by reacting a compound ofFormula XXIII with a strong base (e.g. n-butyllithium) and benzylchloroformate in an inert solvent (e.g. THF), and further debenzylationby hydrogenating the obtained benzyl ester with hydrogen, in thepresence of a catalyst (e.g. 200% Pd(OH)₂/C) at room temperature. Theproduct may be isolated by filtration and evaporation.

Step-4—Synthesis of Compound of Formula XXVIII

Compound of Formula XXVIII may be synthesized by reacting a compound ofFormula XXVII with an amine (e.g. benzylamine) in a polar aproticsolvent (e.g. DMF) in an inert atmosphere, in presence of an activatingagent (e.g. PyBroP (Bromotri(pyrrolidino)phosphoniumhexafluorophosphate) following the procedure described by Coste et. al.,J. Org. Chem., 1994, 59, 2437.

Step-5—Synthesis of Compound of Formula Ia

Compound of Formula Ia, where R⁵ is C(O)NR²⁵R²⁶, may be synthesized bycleaving the protective group (e.g. TIPS) of a compound of FormulaXXVIII with appropriate reagents (e.g. TBAF) and isolating the product(e.g. extraction and silica gel column chromatography).

Example 98 Synthesis of Compounds of Formula Ia where R⁵ is CH₂NHR²⁵R²⁶

Step-1—Synthesis of Compound of Formula XXIII

Compound of Formula XXIII, where P is a protecting group, is synthesizedby reacting compound 1 with a base (e.g. sodium hydride) in a solvent(e.g. THF), followed by an appropriate reagent (P—X, e.g.triisopropylsilylchloride) for introduction of a protecting group. Thereaction is allowed to proceed, typically at room temperature, for 8-12hours and the desired product is isolated by standard procedures (e.g.extraction and silica gel column chromatography) (Greene, T. W.; Wuts,P.G.M. Protective Groups in Organic Synthesis 1, 3^(rd) ed.; John Wiley& Sons: New York, 1981).

Step-2 Synthesis of Compound of Formula XXVI

Compound of Formula XXVI may be synthesized by reacting a compound ofFormula XXIII with sodium cyanide in a polar aprotic solvent (e.g. DMF)in an inert atmosphere, in presence of a catalyst (e.g.Tris(dibenzylideneacetone)dipalladium(0) or cuprous iodide) followingthe procedure described by Buchwald et, al., J. Am. Chem. Soc., 2003,125, 2890-2891, by substituting 5-bromo-7-azaindole for 5-bromo-indole.

Step-3—Synthesis of Compound of Formula XXIX

Compound of Formula XXIX can be synthesized from a compound of FormulaXXVI under hydrogenation conditions using a catalyst (e.g. PtO₂) in anatmosphere of H₂ as described by Secrist III et. al., J. Org. Chem.,1972, 37, 335-336.

Step-4—Synthesis of Compound of Formula XXX

Compound of Formula XXX can be synthesized from a compound of FormulaXXIX with an electrophilic reagent (e.g. benzyl bromide, benzenesulfonylchloride, benzoyl chloride, phenyl isocyanate, phenyl isothiocyanate) ina polar aprotic solvent (e.g. DMF) in an inert atmosphere, in thepresence of a base (e.g. K₂CO₃, Et₃N). The product can be isolated bystandard methods (e.g. aqueous work up and silica gel columnchromatography).

Step-5—Synthesis of Compound of Formula Ia

Compound of Formula Ia, where R⁵ is CH₂NHR²⁵R²⁶, can be synthesized froma compound of Formula XXX with an electrophilic reagent (e.g. benzylbromide, benzenesulfonyl chloride, benzoyl chloride, phenyl isocyanate,phenyl isothiocyanate) in a polar aprotic solvent (e.g. DMF) in an inertatmosphere, in the presence of a base (e.g. K₂CO₃, Et₃N), followed bydeprotection of the protecting group with appropriate conditions (e.g.tetra-n-butylammonium fluoride) and purification by conventional means(e.g. silica gel chromatography).

Example 99 Synthesis of Compounds of Formula Ia where R⁵ is OR²⁵

Step-1—Synthesis of Compound of Formula Ia, where R⁵ is OR¹⁵

A compound of Formula Ia, where R⁵ is OR²⁵, is synthesized by reactingcompound 1 with a reagent of formula R²⁵OH (e.g. methanol) in thepresence of base (e.g. sodium methoxide) and copper (1) bromide in asolvent (e.g. N,N-dimethylformamide) typically with heating to refluxfor 2-8 hours as described by Mazeas, et. al, in Heterocycles, 1999,50:1065. The desired intermediate is purified by conventional means(e.g. silica gel column chromatography).

Example 100 Synthesis of Compounds of Formula Ia where R⁵ is SR²⁵

Compound of Formula Ia, where R⁵ is SR²⁵, can be prepared by reactingcompound 1 with a strong base (e.g. potassium hydride or t-butyllithium) and dialkyldisulfides (e.g. dimethyldisulfane) or thiophenols(e.g. 4-methoxythiophenol) in a polar aprotic solvent (e.g.N,N-dimethylformamide) in an inert atmosphere following the proceduredescribed by Yang et, al., Heterocycles, 1992, 34, 1169, by substituting5-bromo-7-azaindole for 5-bromo-indole.

Example 101 Synthesis of Compounds of Formula Ia where R⁵ is S(O)R²⁵ orS(O)₂R²

Compounds of Formula Ia, where R⁵ is S(O)R²⁵, or S(O)₂R² can be preparedby reacting compound of Formula Ia, where R⁵ is SR²⁵, with 1 or 2equivalents of oxidizing agent (e.g. Oxone), respectively, in a polarsolvent (e.g. DMF), using standard procedures.

Example 102 Synthesis of Compound of Formula Ic, where Y³ is C(O) orCl₂; Y⁶ is NH; and R²⁷ is as Defined in Paragraph [0020]

Step-1 Synthesis of Compound of Formula XXXI

Compound of Formula XXXI in turn can be prepared by reacting6-bromo-7-azaindole (Minakata, S., et al, Synthesis, 1992, p661-663)with an appropriate nucleophile (e.g. acid chlorides, alkyl halides, andthe like) in polar aprotic solvents (e.g. THF, DMF) in the presence of aLewis acid (e.g. AlCl₃, InCl₃ etc.). The product may be isolated byfollowing standard procedures (work up and silica gel columnchromatography).

Step-2 Synthesis of Compound of Formula Ic

Compound of Formula Ic can be prepared by reacting compound of FormulaXXXI with R²⁷NH₂, under Buckwald reaction conditions (Palladium tetrakistrialkylphosphine and a base). The product may be isolated by followingstandard procedures (work up and silica gel column chromatography).

Example 103 Synthesis of Compound of Formula Id, where Y³ is C(O) orCH₂; Y² is CH₂; and R²⁷ is as Defined in Paragraph [0024]

Step-1 Synthesis of Compound of Formula XXXI

Compound of Formula XXXII can be prepared from 2-methyl-7-azaindole(Clemo, S; J. Chem. Soc., 1945, p 603-607) by reacting withN-bromosuccinimide in carbon tetrachloride followed by the reaction ofthe di bromo compound with a nucleophile (e.g. amine, alkoxy, phenoxy,etc). The product may be isolated by following standard procedures (workup and silica gel column chromatography).

Step-2 Synthesis of Compound of Formula Id

Compound of Formula XXXII can be reacted with a lithium reagent (e.g.butyl lithium) followed by the reaction with an aldehyde to provide thekey intermediate to compound of Formula Id. This intermediate can bereacted with a reducing agent (e.g. trifluoroacetic acid andtriethylsilane) at room temperature overnight to provide a compound ofFormula Id where Y³ is CH₂ as described in Example 79 step-2, or with anoxidizing agent (e.g. Dess-Martin periodane, TEMPO) at room temperaturefor 20 minutes to provide a compound of Formula Id where Y³ is C(O) asdescribed in Example 80.

Example 104 Synthesis of Compound of Formula Ie, where Y⁴ is NH; Y² isCH₂; and R²⁷ is as Defined in Paragraph [0027]

Step-1 Synthesis of Compound of Formula XXXIII

Compound of Formula XXXIII can be prepared by reacting4-chloro-1-phenylsulfonyl-7-azaindole (Mendiola, J., et al.; J. Org.Chem., 2004, p4974-4983) with lithium reagent (e.g. LDA) at lowtemperature (e.g. −40° C.) followed by the addition of an alkyl halide(e.g. benzyl bromide). The product may be isolated by following standardprocedures (work up and silica gel column chromatography).

Step-2 Synthesis of Compound of Formula Ie

Compound of Formula Ie can be prepared by reacting a compound of FormulaXXXIII with an amine of formula R²⁷NH₂ under Buckwald reactionconditions followed by deprotection and isolating the product byfollowing standard procedures (work up and silica gel columnchromatography).

Example 105 Synthesis of Compound of Formula I_(f), where Y⁵ is NH; Y²is CH₂; R²⁷ is as Defined in Paragraph [0030]

Step-1 Synthesis of Compound of Formula XXXI V

Compound of Formula XXXIV can be prepared by reacting a compound ofFormula XXXV with a strong base (e.g. KH, potassium tert-butoxide) in asuitable solvent (e.g. NMP) at ambient temperature (Koradin, C., et.al.; Tetrahedron, 2003, p1571-1588). The product may be isolated byfollowing standard procedures (work up and silica gel columnchromatography).

Step-2 Synthesis of Compound of Formula I_(f)

Compound of Formula I_(f) can be prepared by reacting a compound ofFormula XXXIV with an amine of formula R²⁷NH₂ under Buckwald reactionconditions followed by deprotection and isolating the product byfollowing standard procedures (work up and silica gel columnchromatography).

Example 106 Synthesis of Compound of Formula Ij, where Y⁴ is NH; Y⁵ isO; and R²⁷ is as Defined in Paragraph [0042]

Step-1 Synthesis of Compound of Formula X VI

Compound of Formula XXXVI can be synthesized by reactingN-triisopropylsilyl-4-chloro-5-hydroxy-7-azaindole (L'Heureux, A.,Thibault, C., and Ruel, R.; Tetrahedron Letters, 2004, p2317-2319) withan alcohol (e.g. benzyl alcohol) under Mitsunobu reaction conditions andisolating the product by following standard procedures (work up andsilica gel column chromatography).

Step-2 Synthesis of Compound of Formula Ij

Compound of Formula Ij can be prepared by reacting a compound of FormulaXXXVI with an amine of formula R²⁷NH₂ under Buckwald reaction conditionsfollowed by deprotection and isolating the product by following standardprocedures (work up and silica gel column chromatography).

Additional examples of certain methods contemplated by the presentinvention may be found in the following applications: U.S. Prov. App.No. 60/580,898, filed Jun. 17, 2004; U.S. Prov. App. No. 60/682,076,filed May 17, 2005; U.S. Prov. App. No. 60/682,058, filed May 17, 2005;U.S. Prov. App. No. 60/682,063, filed May 17, 2005; U.S. Prov. App. No.60/682,051, filed May 17, 2005; U.S. Prov. App. No. 60/682,042, filedMay 17, 2005; U.S. Prov. App. No. 60/692,750, filed Jun. 22, 2005; andU.S. Prov. App. No. 60/692,960, filed Jun. 22, 2005; each of which arehereby incorporated by reference herein in their entireties includingall specifications, figures, and tables, and for all purposes.

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Forexample, variations can be made to crystallization or co-crystallizationconditions for Ret and Ret surrogate proteins and/or various kinasedomain sequences can be used. Thus, such additional embodiments arewithin the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practicedin the absence of any clement or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intentionthat in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the invention andwithin the following claims.

That which is claimed is:
 1. A method of treating a patient diagnosedwith metastatic melanoma comprising: (a) identifying a metastaticmelanoma patient who is positive for a ^(V600E)BRAF mutation; and (b)administering to the patient identified in step (a) an effective amountof a sulfonamide compound or a pharmaceutically acceptable salt thereof,whose chemical structure includes a Core Moiety I, as shown below:

in which R¹¹² is amino, substituted amino, aryl, substituted aryl,heteroaryl, substituted heteroaryl, or lower alkyl; R⁸³ is hydrogen,fluoro, or chloro; and

represents a carbon-carbon bond connecting the Core Moiety I with theremainder of the compound, which comprises a hydrocarbon having 8-18carbon atoms and one or more heteroatoms.
 2. The method of claim 1 inwhich R¹¹² is a substituted aryl.
 3. The method of claim 2 in which thesubstituted aryl is a fluorobenzene radical.
 4. The method of claim 2 inwhich the substituted aryl is a difluorobenzene radical.
 5. The methodof claim 2 in which R⁸³ is hydrogen.
 6. The method of claim 1 in whichR¹¹² is a lower alkyl.
 7. The method of claim 1 in which the lower alkylis n-propyl.
 8. The method of claim 7 in which R⁸³ is fluoro.
 9. Themethod of claim 1 in which R¹¹² is a difluorobenzene radical and R⁸³ ishydrogen.
 10. The method of claim 1 in which the remainder of thecompound includes a heteroaryl moiety.
 11. The method of claim 10 inwhich the heteroaryl moiety includes two nitrogen atoms.
 12. The methodof claim 1 in which the patient's cancer has metastasized to thepatient's brain.